[ { "key": "6M8T77S2", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/6M8T77S2", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/6M8T77S2", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Grover et al.", "parsedDate": "2012-02", "numChildren": 0 }, "data": { "key": "6M8T77S2", "version": 1, "itemType": "journalArticle", "title": "Computational evidence to inhibition of human acetyl cholinesterase by withanolide a for Alzheimer treatment", "creators": [ { "creatorType": "author", "firstName": "A", "lastName": "Grover" }, { "creatorType": "author", "firstName": "A", "lastName": "Shandilya" }, { "creatorType": "author", "firstName": "V", "lastName": "Agrawal" }, { "creatorType": "author", "firstName": "V S", "lastName": "Bisaria" }, { "creatorType": "author", "firstName": "D", "lastName": "Sundar" } ], "abstractNote": "Alzheimer's disease (AD), a neurodegenerative disorder, is the most common cause of dementia. So far only five drugs have been approved by US FDA that temporarily slow worsening of symptoms for about six to twelve months. The limited number of therapeutic options for AD drives the exploration of new drugs. Enhancement of the central cholinergic function by the inhibition of acetylcholinesterase is a prominent clinically effective approach for the treatment of AD. Recently withanolide A, a secondary metabolite from the ayurvedic plant Withania somnifera has shown substantial neuro-protective ability. The present study is an attempt to elucidate the cholinesterase inhibition potential of withanolide A along with the associated binding mechanism. Our docking simulation results predict high binding affinity of the ligand to the receptor. Further, long de novo simulations for 10_ns suggest that ligand interaction with the residues Thr78, Trp81, Ser120 and His442 of human acetylcholinesterase, all of which fall under one or other of the active sites/subsites, could be critical for its inhibitory activity. The study provides evidence for consideration of withanolide A as a valuable small ligand molecule in treatment and prevention of AD associated pathology. The present information could be of high value for computational screening of AD drugs with low toxicity to normal cells. Accurate knowledge of the 3D structure of human acetylcholinesterase would further enhance the potential of such analysis in understanding the molecular interaction basis between ligand and receptor.", "publicationTitle": "Journal of Biomolecular Structure & Dynamics", "publisher": "", "place": "", "date": "Feb 2012", "volume": "29", "issue": "4", "section": "", "partNumber": "", "partTitle": "", "pages": "651-662", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "J. Biomol. Struct. Dyn.", "DOI": "", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/22208270", "accessDate": "2012-01-04T10:33:46Z", "PMID": "", "PMCID": "", "ISSN": "1538-0254", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 22208270", "tags": [], "collections": [ "SW64SGCK" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/XB7UZE8E" }, "dateAdded": "2012-01-04T10:33:46Z", "dateModified": "2012-01-04T10:33:46Z" } }, { "key": "5DWVVB2T", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/5DWVVB2T", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/5DWVVB2T", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Kesharwani et al.", "parsedDate": "2010-02-08", "numChildren": 0 }, "data": { "key": "5DWVVB2T", "version": 1, "itemType": "journalArticle", "title": "Differential binding of bispyridinium oxime drugs with acetylcholinesterase", "creators": [ { "creatorType": "author", "firstName": "Manoj K", "lastName": "Kesharwani" }, { "creatorType": "author", "firstName": "Bishwajit", "lastName": "Ganguly" }, { "creatorType": "author", "firstName": "Amit", "lastName": "Das" }, { "creatorType": "author", "firstName": "Tusar", "lastName": "Bandyopadhyay" } ], "abstractNote": "", "publicationTitle": "Acta Pharmacologica Sinica", "publisher": "", "place": "", "date": "2010-02-08", "volume": "31", "issue": "", "section": "", "partNumber": "", "partTitle": "", "pages": "313-328", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "", "DOI": "10.1038/aps.2009.193", "citationKey": "", "url": "http://www.nature.com/doifinder/10.1038/aps.2009.193", "accessDate": "2011-10-20T13:09:37Z", "PMID": "", "PMCID": "", "ISSN": "1671-4083, 1745-7254", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "CrossRef", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/V69R57ZG" }, "dateAdded": "2011-10-20T13:09:37Z", "dateModified": "2011-10-20T13:09:37Z" } }, { "key": "PGC7XE5R", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/PGC7XE5R", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/PGC7XE5R", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Dvir et al.", "parsedDate": "2010-09-06", "numChildren": 0 }, "data": { "key": "PGC7XE5R", "version": 1, "itemType": "journalArticle", "title": "Acetylcholinesterase: from 3D structure to function", "creators": [ { "creatorType": "author", "firstName": "Hay", "lastName": "Dvir" }, { "creatorType": "author", "firstName": "Israel", "lastName": "Silman" }, { "creatorType": "author", "firstName": "Michal", "lastName": "Harel" }, { "creatorType": "author", "firstName": "Terrone L", "lastName": "Rosenberry" }, { "creatorType": "author", "firstName": "Joel L", "lastName": "Sussman" } ], "abstractNote": "By rapid hydrolysis of the neurotransmitter, acetylcholine, acetylcholinesterase terminates neurotransmission at cholinergic synapses. Acetylcholinesterase is a very fast enzyme, functioning at a rate approaching that of a diffusion-controlled reaction. The powerful toxicity of organophosphate poisons is attributed primarily to their potent inhibition of acetylcholinesterase. Acetylcholinesterase inhibitors are utilized in the treatment of various neurological disorders, and are the principal drugs approved thus far by the FDA for management of Alzheimer's disease. Many organophosphates and carbamates serve as potent insecticides, by selectively inhibiting insect acetylcholinesterase. The determination of the crystal structure of Torpedo californica acetylcholinesterase permitted visualization, for the first time, at atomic resolution, of a binding pocket for acetylcholine. It also allowed identification of the active site of acetylcholinesterase, which, unexpectedly, is located at the bottom of a deep gorge lined largely by aromatic residues. The crystal structure of recombinant human acetylcholinesterase in its apo-state is similar in its overall features to that of the Torpedo enzyme; however, the unique crystal packing reveals a novel peptide sequence which blocks access to the active-site gorge.", "publicationTitle": "Chemico-Biological Interactions", "publisher": "", "place": "", "date": "Sep 6, 2010", "volume": "187", "issue": "1-3", "section": "", "partNumber": "", "partTitle": "", "pages": "10-22", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Chem. Biol. Interact.", "DOI": "10.1016/j.cbi.2010.01.042", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/20138030", "accessDate": "2011-10-20T11:47:42Z", "PMID": "", "PMCID": "", "ISSN": "1872-7786", "archive": "", "archiveLocation": "", "shortTitle": "Acetylcholinesterase", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 20138030", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Animals", "type": 1 }, { "tag": "Apoenzymes", "type": 1 }, { "tag": "Catalytic Domain", "type": 1 }, { "tag": "Crystallography, X-Ray", "type": 1 }, { "tag": "Humans", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Protein Structure, Quaternary", "type": 1 }, { "tag": "Static Electricity", "type": 1 }, { "tag": "Structure-Activity Relationship", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/67CNJRKE" }, "dateAdded": "2011-10-20T11:47:42Z", "dateModified": "2011-10-20T11:47:42Z" } }, { "key": "H4SFG983", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/H4SFG983", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/H4SFG983", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Piana et al.", "parsedDate": "2011-05-04", "numChildren": 0 }, "data": { "key": "H4SFG983", "version": 1, "itemType": "journalArticle", "title": "How robust are protein folding simulations with respect to force field parameterization?", "creators": [ { "creatorType": "author", "firstName": "Stefano", "lastName": "Piana" }, { "creatorType": "author", "firstName": "Kresten", "lastName": "Lindorff-Larsen" }, { "creatorType": "author", "firstName": "David E", "lastName": "Shaw" } ], "abstractNote": "Molecular dynamics simulations hold the promise of providing an atomic-level description of protein folding that cannot easily be obtained from experiments. Here, we examine the extent to which the molecular mechanics force field used in such simulations might influence the observed folding pathways. To that end, we performed equilibrium simulations of a fast-folding variant of the villin headpiece using four different force fields. In each simulation, we observed a large number of transitions between the unfolded and folded states, and in all four cases, both the rate of folding and the structure of the native state were in good agreement with experiments. We found, however, that the folding mechanism and the properties of the unfolded state depend substantially on the choice of force field. We thus conclude that although it is important to match a single, experimentally determined structure and folding rate, this does not ensure that a given simulation will provide a unique and correct description of the full free-energy surface and the mechanism of folding.", "publicationTitle": "Biophysical Journal", "publisher": "", "place": "", "date": "May 4, 2011", "volume": "100", "issue": "9", "section": "", "partNumber": "", "partTitle": "", "pages": "L47-49", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Biophys. J.", "DOI": "10.1016/j.bpj.2011.03.051", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/21539772", "accessDate": "2011-09-27T09:37:03Z", "PMID": "", "PMCID": "", "ISSN": "1542-0086", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 21539772", "tags": [ { "tag": "Algorithms", "type": 1 }, { "tag": "Biomechanics", "type": 1 }, { "tag": "Computer Simulation", "type": 1 }, { "tag": "Kinetics", "type": 1 }, { "tag": "Microfilament Proteins", "type": 1 }, { "tag": "Protein Folding", "type": 1 }, { "tag": "Protein Structure, Secondary", "type": 1 }, { "tag": "Thermodynamics", "type": 1 } ], "collections": [ "UK5R76N3" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/6GH6KWR8" }, "dateAdded": "2011-09-27T09:37:03Z", "dateModified": "2011-09-27T09:37:03Z" } }, { "key": "U98EUH6J", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/U98EUH6J", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/U98EUH6J", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Arnautova et al.", "parsedDate": "2006-03-16", "numChildren": 0 }, "data": { "key": "U98EUH6J", "version": 1, "itemType": "journalArticle", "title": "A new force field (ECEPP-05) for peptides, proteins, and organic molecules", "creators": [ { "creatorType": "author", "firstName": "Yelena A", "lastName": "Arnautova" }, { "creatorType": "author", "firstName": "Anna", "lastName": "Jagielska" }, { "creatorType": "author", "firstName": "Harold A", "lastName": "Scheraga" } ], "abstractNote": "Parametrization and testing of a new all-atom force field for organic molecules and peptides with fixed bond lengths and bond angles are described. The van der Waals parameters for both the organic molecules and the peptides were taken from J. Phys. Chem. B 2003, 107, 7143 and J. Phys. Chem. B 2004, 108, 12181. First, the values of the 1-4 nonbonded and electrostatic scale factors appropriate to the new force field were determined by computing the conformational energies of six model molecules, namely, ethanol, ethylamine, propanol, propylamine, 1,2-ethanediol, and 1,3-propanediol with different values of these factors. The partial atomic charges of these molecules were obtained by fitting to the electrostatic potentials calculated with the HF/6-31G quantum-mechanical method. Two different charge models (single- and multiple-conformation-derived) were also considered. We demonstrated that the charge model has a stronger effect on the conformational energies than the 1-4 scaling. The choice of a charge model affected the conformational energies of even the smallest molecules considered, whereas the effect of the 1-4 electrostatic or nonbonded scaling was apparent only for 1,3-propanediol. The best agreement with high-level ab initio data was obtained with the multiple-conformation-derived charges and with no scaling of the 1-4 nonbonded or electrostatic interactions (scale factors of 1.0). Next, the torsional parameters of a large number of neutral and charged organic molecules, assumed to be models of the side chains of the 20 naturally occurring amino acids, were computed by fitting to rotational energy profiles obtained from ab initio MP2/6-31G calculations. The quality of the fits was high with average errors for torsional profiles of less than 0.2 kcal/mol. To derive the torsional parameters for the peptide backbone, the partial atomic charges of the 20 neutral and charged amino acids were obtained by fitting to the electrostatic potentials of terminally blocked amino acids using the HF/6-31G quantum-mechanical method. Then, the phi-psi energy maps of Ac-Ala-NMe and Ac-Gly-NMe were computed using MP2/6-31G//HF/6-31G quantum-mechanical methods. The phi-psi energy map of Ac-Ala-NMe was used for refinement of the nonbonded parameters for the backbone nitrogen and hydrogen bonded to it. Subsequently, the main-chain torsional parameters were obtained by fitting the molecular mechanics energies to the phi-psi energy maps of Ac-Ala-NMe and Ac-Gly-NMe. The transferability of the entire force field was demonstrated by reproducing the main energy minima of terminally blocked Ala3 from the literature. The performance of the force field was also evaluated by simulating crystal structures of small peptides. By comparison of simulated and experimental data, examination of the torsional-angle and atom-positional root-mean-square deviations of the energy-minimized crystal structures from the corresponding X-ray model structures demonstrated high accuracy of the force field.", "publicationTitle": "The Journal of Physical Chemistry. B", "publisher": "", "place": "", "date": "Mar 16, 2006", "volume": "110", "issue": "10", "section": "", "partNumber": "", "partTitle": "", "pages": "5025-5044", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "J Phys Chem B", "DOI": "10.1021/jp054994x", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/16526746", "accessDate": "2011-09-27T09:36:46Z", "PMID": "", "PMCID": "", "ISSN": "1520-6106", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 16526746", "tags": [ { "tag": "Algorithms", "type": 1 }, { "tag": "Crystallography, X-Ray", "type": 1 }, { "tag": "Hydrogen Bonding", "type": 1 }, { "tag": "Models, Chemical", "type": 1 }, { "tag": "Molecular Conformation", "type": 1 }, { "tag": "Organic Chemicals", "type": 1 }, { "tag": "Peptides", "type": 1 }, { "tag": "Proteins", "type": 1 }, { "tag": "Quantum Theory", "type": 1 }, { "tag": "Static Electricity", "type": 1 } ], "collections": [ "UK5R76N3" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/2K46RBAC" }, "dateAdded": "2011-09-27T09:36:46Z", "dateModified": "2011-09-27T09:36:46Z" } }, { "key": "TA9N8R5C", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/TA9N8R5C", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/TA9N8R5C", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Guvench and MacKerell", "parsedDate": "2008", "numChildren": 0 }, "data": { "key": "TA9N8R5C", "version": 1, "itemType": "journalArticle", "title": "Comparison of protein force fields for molecular dynamics simulations", "creators": [ { "creatorType": "author", "firstName": "Olgun", "lastName": "Guvench" }, { "creatorType": "author", "firstName": "Alexander D, Jr", "lastName": "MacKerell" } ], "abstractNote": "In the context of molecular dynamics simulations of proteins, the term \"force field\" refers to the combination of a mathematical formula and associated parameters that are used to describe the energy of the protein as a function of its atomic coordinates. In this review, we describe the functional forms and parameterization protocols of the widely used biomolecular force fields Amber, CHARMM, GROMOS, and OPLS-AA. We also summarize the ability of various readily available noncommercial molecular dynamics packages to perform simulations using these force fields, as well as to use modern methods for the generation of constant-temperature, constant-pressure ensembles and to treat long-range interactions. Finally, we finish with a discussion of the ability of these force fields to support the modeling of proteins in conjunction with nucleic acids, lipids, carbohydrates, and/or small molecules.", "publicationTitle": "Methods in Molecular Biology (Clifton, N.J.)", "publisher": "", "place": "", "date": "2008", "volume": "443", "issue": "", "section": "", "partNumber": "", "partTitle": "", "pages": "63-88", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Methods Mol. Biol.", "DOI": "10.1007/978-1-59745-177-2_4", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/18446282", "accessDate": "2011-09-27T09:36:06Z", "PMID": "", "PMCID": "", "ISSN": "1064-3745", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 18446282", "tags": [ { "tag": "Carbohydrates", "type": 1 }, { "tag": "Computer Simulation", "type": 1 }, { "tag": "Lipids", "type": 1 }, { "tag": "Nucleic Acids", "type": 1 }, { "tag": "Protein Conformation", "type": 1 }, { "tag": "Protein Folding", "type": 1 }, { "tag": "Proteins", "type": 1 }, { "tag": "Software", "type": 1 }, { "tag": "Temperature", "type": 1 } ], "collections": [ "UK5R76N3" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/58I5Z4UG" }, "dateAdded": "2011-09-27T09:36:06Z", "dateModified": "2011-09-27T09:36:06Z" } }, { "key": "QCJQ6ZU6", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/QCJQ6ZU6", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/QCJQ6ZU6", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Wang et al.", "parsedDate": "2006-04-30", "numChildren": 0 }, "data": { "key": "QCJQ6ZU6", "version": 1, "itemType": "journalArticle", "title": "Strike a balance: optimization of backbone torsion parameters of AMBER polarizable force field for simulations of proteins and peptides", "creators": [ { "creatorType": "author", "firstName": "Zhi-Xiang", "lastName": "Wang" }, { "creatorType": "author", "firstName": "Wei", "lastName": "Zhang" }, { "creatorType": "author", "firstName": "Chun", "lastName": "Wu" }, { "creatorType": "author", "firstName": "Hongxing", "lastName": "Lei" }, { "creatorType": "author", "firstName": "Piotr", "lastName": "Cieplak" }, { "creatorType": "author", "firstName": "Yong", "lastName": "Duan" } ], "abstractNote": "Based on the AMBER polarizable model (ff02), we have re-optimized the parameters related to the main-chain (Phi, Psi) torsion angles by fitting to the Boltzmann-weighted average quantum mechanical (QM) energies of the important regions (i.e., beta, P(II), alpha(R), and alpha(L) regions). Following the naming convention of the AMBER force field series, this release will be called ff02pol.rl The force field has been assessed both by energetic comparison against the QM data and by the replica exchange molecular dynamics simulations of short alanine peptides in water. For Ace-Ala-Nme, the simulated populations in the beta, P(II) and alpha(R) regions were approximately 30, 43, and 26%, respectively. For Ace-(Ala)(7)-Nme, the populations in these three regions were approximately 24, 49, and 26%. Both were in qualitative agreement with the NMR and CD experimental conclusions. In comparison with the previous force field, ff02pol.rl demonstrated good balance among these three important regions. The optimized torsion parameters, together with those in ff02, allow us to carry out simulations on proteins and peptides with the consideration of polarization.", "publicationTitle": "Journal of Computational Chemistry", "publisher": "", "place": "", "date": "Apr 30, 2006", "volume": "27", "issue": "6", "section": "", "partNumber": "", "partTitle": "", "pages": "781-790", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "J Comput Chem", "DOI": "10.1002/jcc.20386", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/16526038", "accessDate": "2011-09-27T09:35:56Z", "PMID": "", "PMCID": "", "ISSN": "0192-8651", "archive": "", "archiveLocation": "", "shortTitle": "Strike a balance", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 16526038", "tags": [ { "tag": "Computer Simulation", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Peptides", "type": 1 }, { "tag": "Protein Conformation", "type": 1 }, { "tag": "Proteins", "type": 1 }, { "tag": "Torsion Abnormality", "type": 1 } ], "collections": [ "UK5R76N3" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/4Q24TSBP" }, "dateAdded": "2011-09-27T09:35:56Z", "dateModified": "2011-09-27T09:35:56Z" } }, { "key": "MG3WRBVU", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/MG3WRBVU", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/MG3WRBVU", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Ponomarev and Kaminski", "parsedDate": "2011-05-10", "numChildren": 0 }, "data": { "key": "MG3WRBVU", "version": 1, "itemType": "journalArticle", "title": "Polarizable Simulations with Second order Interaction Model (POSSIM) force field: Developing parameters for alanine peptides and protein backbone", "creators": [ { "creatorType": "author", "firstName": "Sergei Y", "lastName": "Ponomarev" }, { "creatorType": "author", "firstName": "George A", "lastName": "Kaminski" } ], "abstractNote": "A previously introduced POSSIM (POlarizable Simulations with Second order Interaction Model) force field has been extended to include parameters for alanine peptides and protein backbones. New features were introduced into the fitting protocol, as compared to the previous generation of the polarizable force field for proteins. A reduced amount of quantum mechanical data was employed in fitting the electrostatic parameters. Transferability of the electrostatics between our recently developed NMA model and the protein backbone was confirmed. Binding energy and geometry for complexes of alanine dipeptide with a water molecule were estimated and found in a good agreement with high-level quantum mechanical results (for example, the intermolecular distances agreeing within ca. 0.06Å). Following the previously devised procedure, we calculated average errors in alanine di- and tetra-peptide conformational energies and backbone angles and found the agreement to be adequate (for example, the alanine tetrapeptide extended-globular conformational energy gap was calculated to be 3.09 kcal/mol quantim mechanically and 3.14 kcal/mol with the POSSIM force field). However, we have now also included simulation of a simple alpha-helix in both gas-phase and water as the ultimate test of the backbone conformational behavior. The resulting alanine and protein backbone force field is currently being employed in further development of the POSSIM fast polarizable force field for proteins.", "publicationTitle": "Journal of Chemical Theory and Computation", "publisher": "", "place": "", "date": "May 10, 2011", "volume": "7", "issue": "5", "section": "", "partNumber": "", "partTitle": "", "pages": "1415-1427", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "", "DOI": "10.1021/ct1007197", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/21743799", "accessDate": "2011-09-27T09:34:57Z", "PMID": "", "PMCID": "", "ISSN": "1549-9626", "archive": "", "archiveLocation": "", "shortTitle": "Polarizable Simulations with Second order Interaction Model (POSSIM) force field", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 21743799", "tags": [], "collections": [ "UK5R76N3" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/K3PHFR8M" }, "dateAdded": "2011-09-27T09:34:57Z", "dateModified": "2011-09-27T09:34:57Z" } }, { "key": "TRXKP269", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/TRXKP269", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/TRXKP269", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Koellner et al.", "parsedDate": "2000-02-18", "numChildren": 0 }, "data": { "key": "TRXKP269", "version": 1, "itemType": "journalArticle", "title": "Active-site gorge and buried water molecules in crystal structures of acetylcholinesterase from Torpedo californica", "creators": [ { "creatorType": "author", "firstName": "G", "lastName": "Koellner" }, { "creatorType": "author", "firstName": "G", "lastName": "Kryger" }, { "creatorType": "author", "firstName": "C B", "lastName": "Millard" }, { "creatorType": "author", "firstName": "I", "lastName": "Silman" }, { "creatorType": "author", "firstName": "J L", "lastName": "Sussman" }, { "creatorType": "author", "firstName": "T", "lastName": "Steiner" } ], "abstractNote": "Buried water molecules and the water molecules in the active-site gorge are analyzed for five crystal structures of acetylcholinesterase from Torpedo californica in the resolution range 2.2-2.5 A (native enzyme, and four inhibitor complexes). A total of 45 buried hydration sites are identified, which are populated with between 36 and 41 water molecules. About half of the buried water is located in a distinct region neighboring the active-site gorge. Most of the buried water molecules are very well conserved among the five structures, and have low displacement parameters, B, of magnitudes similar to those of the main-chain atoms of the central beta-sheet structure. The active-site gorge of the native enzyme is filled with over 20 water molecules, which have poor hydrogen-bond coordination with an average of 2.9 polar contacts per water molecule. Upon ligand binding, distinct groups of these water molecules are displaced, whereas the others remain in positions similar to those that they occupy in the native enzyme. Possible roles of the buried water molecules are discussed, including their possible action as a lubricant to allow large-amplitude fluctuations of the loop structures forming the gorge wall. Such fluctuations are required to facilitate traffic of substrate, products and water molecules to and from the active-site. Because of their poor coordination, the gorge water molecules can be considered as \"activated\" as compared to bulk water. This should allow their easy displacement by incoming substrate. The relatively loose packing of the gorge water molecules leaves numerous small voids, and more efficient space-filling by substrates and inhibitors may be a major driving force of ligand binding.", "publicationTitle": "Journal of Molecular Biology", "publisher": "", "place": "", "date": "Feb 18, 2000", "volume": "296", "issue": "2", "section": "", "partNumber": "", "partTitle": "", "pages": "713-735", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "J. Mol. Biol.", "DOI": "10.1006/jmbi.1999.3468", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/10669619", "accessDate": "2011-09-27T09:30:48Z", "PMID": "", "PMCID": "", "ISSN": "0022-2836", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 10669619", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Amino Acid Sequence", "type": 1 }, { "tag": "Animals", "type": 1 }, { "tag": "Binding Sites", "type": 1 }, { "tag": "Cholinesterase Inhibitors", "type": 1 }, { "tag": "Crystallization", "type": 1 }, { "tag": "Crystallography, X-Ray", "type": 1 }, { "tag": "Edrophonium", "type": 1 }, { "tag": "Hydrogen Bonding", "type": 1 }, { "tag": "Indans", "type": 1 }, { "tag": "Ligands", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Molecular Sequence Data", "type": 1 }, { "tag": "Piperidines", "type": 1 }, { "tag": "Protein Structure, Secondary", "type": 1 }, { "tag": "Reproducibility of Results", "type": 1 }, { "tag": "Sesquiterpenes", "type": 1 }, { "tag": "Static Electricity", "type": 1 }, { "tag": "Torpedo", "type": 1 }, { "tag": "Water", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/RSTEBI3J" }, "dateAdded": "2011-09-27T09:30:48Z", "dateModified": "2011-09-27T09:30:48Z" } }, { "key": "2KSADQ3I", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/2KSADQ3I", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/2KSADQ3I", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Eyal et al.", "parsedDate": "2005-08-12", "numChildren": 0 }, "data": { "key": "2KSADQ3I", "version": 1, "itemType": "journalArticle", "title": "The limit of accuracy of protein modeling: influence of crystal packing on protein structure", "creators": [ { "creatorType": "author", "firstName": "Eran", "lastName": "Eyal" }, { "creatorType": "author", "firstName": "Sergey", "lastName": "Gerzon" }, { "creatorType": "author", "firstName": "Vladimir", "lastName": "Potapov" }, { "creatorType": "author", "firstName": "Marvin", "lastName": "Edelman" }, { "creatorType": "author", "firstName": "Vladimir", "lastName": "Sobolev" } ], "abstractNote": "The size of the protein database (PDB) makes it now feasible to arrive at statistical conclusions regarding structural effects of crystal packing. These effects are relevant for setting upper practical limits of accuracy on protein modeling. Proteins whose crystals have more than one molecule in the asymmetric unit or whose structures were determined at least twice by X-ray crystallography were paired and their differences analyzed. We demonstrate a clear influence of crystal environment on protein structure, including backbone conformations, hinge-like motions and side-chain conformations. The positions of surface water molecules tend to be variable in different crystal environments while those of ligands are not. Structures determined by independent groups vary more than structures determined by the same authors. The use of different refinement methods is a major source for this effect. Our pair-wise analysis derives a practical limit to the accuracy of protein modeling. For different crystal forms, the limit of accuracy (C(alpha), root-mean-square deviation (RMSD)) is approximately 0.8A for the entire protein, which includes approximately 0.3A due to crystal packing. For organized secondary elements, the upper limit of C(alpha) RMSD is 0.5-0.6A while for loops or protein surface it reaches 1.0A. Twenty percent of exposed side- chains exhibit different chi(1+2) conformations with approximately half of the effect also resulting from crystal packing. A web based tool for analysis and graphic presentation of surface areas of crystal contacts is available (http://ligin.weizmann.ac.il/cryco).", "publicationTitle": "Journal of Molecular Biology", "publisher": "", "place": "", "date": "Aug 12, 2005", "volume": "351", "issue": "2", "section": "", "partNumber": "", "partTitle": "", "pages": "431-442", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "J. Mol. Biol.", "DOI": "10.1016/j.jmb.2005.05.066", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/16005885", "accessDate": "2011-09-27T09:28:50Z", "PMID": "", "PMCID": "", "ISSN": "0022-2836", "archive": "", "archiveLocation": "", "shortTitle": "The limit of accuracy of protein modeling", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 16005885", "tags": [ { "tag": "Computational Biology", "type": 1 }, { "tag": "Crystallography, X-Ray", "type": 1 }, { "tag": "Databases, Protein", "type": 1 }, { "tag": "Ligands", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Molecular Conformation", "type": 1 }, { "tag": "Protein Conformation", "type": 1 }, { "tag": "Protein Structure, Secondary", "type": 1 }, { "tag": "Protein Structure, Tertiary", "type": 1 }, { "tag": "Proteins", "type": 1 }, { "tag": "Proteomics", "type": 1 }, { "tag": "Software", "type": 1 }, { "tag": "Solvents", "type": 1 }, { "tag": "Water", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/ZRMTKXGH" }, "dateAdded": "2011-09-27T09:28:50Z", "dateModified": "2011-09-27T09:28:50Z" } }, { "key": "PS5UT5V7", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/PS5UT5V7", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/PS5UT5V7", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Bartolucci et al.", "parsedDate": "1999-05-04", "numChildren": 0 }, "data": { "key": "PS5UT5V7", "version": 1, "itemType": "journalArticle", "title": "\"Back door\" opening implied by the crystal structure of a carbamoylated acetylcholinesterase", "creators": [ { "creatorType": "author", "firstName": "C", "lastName": "Bartolucci" }, { "creatorType": "author", "firstName": "E", "lastName": "Perola" }, { "creatorType": "author", "firstName": "L", "lastName": "Cellai" }, { "creatorType": "author", "firstName": "M", "lastName": "Brufani" }, { "creatorType": "author", "firstName": "D", "lastName": "Lamba" } ], "abstractNote": "The crystal structure of Torpedo californica (Tc) acetylcholinesterase (AChE) carbamoylated by the physostigmine analogue 8-(cis-2,6-dimethylmorpholino)octylcarbamoyleseroline (MF268) is reported at 2.7 A resolution. In the X-ray structure, the dimethylmorpholinooctylcarbamic moiety of MF268 is covalently bound to the catalytic serine, which is located at the bottom of a long and narrow gorge. The alkyl chain of the inhibitor fills the upper part of the gorge, blocking the entrance of the active site. This prevents eseroline, the leaving group of the carbamoylation process, from exiting through this path. Surprisingly, the relatively bulky eseroline is not found in the crystal structure, thus implying the existence of an alternative route for its clearance. This represents indirect evidence that a \"back door\" opening may occur and shows that the release of products via a \"back door\" is a likely alternative for this enzyme. However, its relevance as far as the mechanism of substrate hydrolysis is concerned needs to be established. This study suggests that the use of properly designed acylating inhibitors, which can block the entrance of catalytic sites, may be exploited as a general approach for investigating the existence of \"back doors\" for the clearance of products.", "publicationTitle": "Biochemistry", "publisher": "", "place": "", "date": "May 4, 1999", "volume": "38", "issue": "18", "section": "", "partNumber": "", "partTitle": "", "pages": "5714-5719", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Biochemistry", "DOI": "10.1021/bi982723p", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/10231521", "accessDate": "2011-09-27T09:21:05Z", "PMID": "", "PMCID": "", "ISSN": "0006-2960", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 10231521", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Animals", "type": 1 }, { "tag": "Binding Sites", "type": 1 }, { "tag": "Carbamates", "type": 1 }, { "tag": "Catalysis", "type": 1 }, { "tag": "Choline", "type": 1 }, { "tag": "Cholinesterase Inhibitors", "type": 1 }, { "tag": "Crystallization", "type": 1 }, { "tag": "Crystallography, X-Ray", "type": 1 }, { "tag": "Decamethonium Compounds", "type": 1 }, { "tag": "Enzyme Stability", "type": 1 }, { "tag": "Hydrolysis", "type": 1 }, { "tag": "Macromolecular Substances", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Morpholines", "type": 1 }, { "tag": "Neuromuscular Depolarizing Agents", "type": 1 }, { "tag": "Protein Conformation", "type": 1 }, { "tag": "Torpedo", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/TFTFVH87" }, "dateAdded": "2011-09-27T09:21:05Z", "dateModified": "2011-09-27T09:21:05Z" } }, { "key": "GP8MX97T", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/GP8MX97T", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/GP8MX97T", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Silman and Sussman", "parsedDate": "2008-09-25", "numChildren": 0 }, "data": { "key": "GP8MX97T", "version": 1, "itemType": "journalArticle", "title": "Acetylcholinesterase: how is structure related to function?", "creators": [ { "creatorType": "author", "firstName": "Israel", "lastName": "Silman" }, { "creatorType": "author", "firstName": "Joel L", "lastName": "Sussman" } ], "abstractNote": "In accordance with its biological role, termination of neurotransmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter, acetylcholine, acetylcholinesterase is one of nature's most efficient enzymes. Solution of its three-dimensional structure revealed that its active site is located at the bottom of a deep and narrow gorge. Such an architecture was unanticipated in view of its high turnover number. The present review examines how the highly specialized structure of acetylcholinesterase, with its sequestered active site, contributes to its catalytic efficacy, and discusses how the traffic of substrate and products to and from the active site is controlled.", "publicationTitle": "Chemico-Biological Interactions", "publisher": "", "place": "", "date": "Sep 25, 2008", "volume": "175", "issue": "1-3", "section": "", "partNumber": "", "partTitle": "", "pages": "3-10", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Chem. Biol. Interact.", "DOI": "10.1016/j.cbi.2008.05.035", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/18586019", "accessDate": "2011-09-27T09:20:00Z", "PMID": "", "PMCID": "", "ISSN": "0009-2797", "archive": "", "archiveLocation": "", "shortTitle": "Acetylcholinesterase", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 18586019", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Catalytic Domain", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Structure-Activity Relationship", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/T6JB4CKU" }, "dateAdded": "2011-09-27T09:20:00Z", "dateModified": "2011-09-27T09:20:00Z" } }, { "key": "DFGSEAVA", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/DFGSEAVA", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/DFGSEAVA", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "McCammon", "parsedDate": "2011", "numChildren": 0 }, "data": { "key": "DFGSEAVA", "version": 1, "itemType": "journalArticle", "title": "Gated Diffusion-controlled Reactions", "creators": [ { "creatorType": "author", "firstName": "J Andrew", "lastName": "McCammon" } ], "abstractNote": "The binding and active sites of proteins are often dynamically occluded by motion of the nearby polypeptide. A variety of theoretical and computational methods have been developed to predict rates of ligand binding and reactivity in such cases. Two general approaches exist, \"protein centric\" approaches that explicitly treat only the protein target, and more detailed dynamical simulation approaches in which target and ligand are both treated explicitly. This mini-review describes recent work in this area and some of the biological implications.", "publicationTitle": "BMC Biophysics", "publisher": "", "place": "", "date": "2011", "volume": "4", "issue": "", "section": "", "partNumber": "", "partTitle": "", "pages": "4", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "BMC Biophys", "DOI": "10.1186/2046-1682-4-4", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/21595999", "accessDate": "2011-09-27T09:19:50Z", "PMID": "", "PMCID": "", "ISSN": "2046-1682", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 21595999", "tags": [], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/7D5QAT77" }, "dateAdded": "2011-09-27T09:19:50Z", "dateModified": "2011-09-27T09:19:50Z" } }, { "key": "AAMRXAZ2", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/AAMRXAZ2", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/AAMRXAZ2", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Shen et al.", "parsedDate": "2002-06", "numChildren": 0 }, "data": { "key": "AAMRXAZ2", "version": 1, "itemType": "journalArticle", "title": "Molecular dynamics of acetylcholinesterase", "creators": [ { "creatorType": "author", "firstName": "Tongye", "lastName": "Shen" }, { "creatorType": "author", "firstName": "Kaihsu", "lastName": "Tai" }, { "creatorType": "author", "firstName": "Richard H", "lastName": "Henchman" }, { "creatorType": "author", "firstName": "J Andrew", "lastName": "McCammon" } ], "abstractNote": "Molecular dynamics simulations are leading to a deeper understanding of the activity of the enzyme acetylcholinesterase. Simulations have shown how breathing motions in the enzyme facilitate the displacement of substrate from the surface of the enzyme to the buried active site. The most recent work points to the complex and spatially extensive nature of such motions and suggests possible modes of regulation of the activity of the enzyme.", "publicationTitle": "Accounts of Chemical Research", "publisher": "", "place": "", "date": "Jun 2002", "volume": "35", "issue": "6", "section": "", "partNumber": "", "partTitle": "", "pages": "332-340", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Acc. Chem. Res.", "DOI": "", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/12069617", "accessDate": "2011-09-27T09:19:06Z", "PMID": "", "PMCID": "", "ISSN": "0001-4842", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 12069617", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Animals", "type": 1 }, { "tag": "Catalytic Domain", "type": 1 }, { "tag": "Computer Simulation", "type": 1 }, { "tag": "Humans", "type": 1 }, { "tag": "Motion", "type": 1 }, { "tag": "Protein Binding", "type": 1 }, { "tag": "Protein Conformation", "type": 1 }, { "tag": "Water", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/R3C2X9VE" }, "dateAdded": "2011-09-27T09:19:06Z", "dateModified": "2011-09-27T09:19:06Z" } }, { "key": "2JTX8TKE", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/2JTX8TKE", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/2JTX8TKE", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Gilson et al.", "parsedDate": "1994-03-04", "numChildren": 0 }, "data": { "key": "2JTX8TKE", "version": 1, "itemType": "journalArticle", "title": "Open \"back door\" in a molecular dynamics simulation of acetylcholinesterase", "creators": [ { "creatorType": "author", "firstName": "M K", "lastName": "Gilson" }, { "creatorType": "author", "firstName": "T P", "lastName": "Straatsma" }, { "creatorType": "author", "firstName": "J A", "lastName": "McCammon" }, { "creatorType": "author", "firstName": "D R", "lastName": "Ripoll" }, { "creatorType": "author", "firstName": "C H", "lastName": "Faerman" }, { "creatorType": "author", "firstName": "P H", "lastName": "Axelsen" }, { "creatorType": "author", "firstName": "I", "lastName": "Silman" }, { "creatorType": "author", "firstName": "J L", "lastName": "Sussman" } ], "abstractNote": "The enzyme acetylcholinesterase generates a strong electrostatic field that can attract the cationic substrate acetylcholine to the active site. However, the long and narrow active site gorge seems inconsistent with the enzyme's high catalytic rate. A molecular dynamics simulation of acetylcholinesterase in water reveals the transient opening of a short channel, large enough to pass a water molecule, through a thin wall of the active site near tryptophan-84. This simulation suggests that substrate, products, or solvent could move through this \"back door,\" in addition to the entrance revealed by the crystallographic structure. Electrostatic calculations show a strong field at the back door, oriented to attract the substrate and the reaction product choline and to repel the other reaction product, acetate. Analysis of the open back door conformation suggests a mutation that could seal the back door and thus test the hypothesis that thermal motion of this enzyme may open multiple routes of access to its active site.", "publicationTitle": "Science (New York, N.Y.)", "publisher": "", "place": "", "date": "Mar 4, 1994", "volume": "263", "issue": "5151", "section": "", "partNumber": "", "partTitle": "", "pages": "1276-1278", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Science", "DOI": "", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/8122110", "accessDate": "2011-09-27T09:18:09Z", "PMID": "", "PMCID": "", "ISSN": "0036-8075", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 8122110", "tags": [ { "tag": "Acetylcholine", "type": 1 }, { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Binding Sites", "type": 1 }, { "tag": "Catalysis", "type": 1 }, { "tag": "Choline", "type": 1 }, { "tag": "Computer Simulation", "type": 1 }, { "tag": "Crystallography, X-Ray", "type": 1 }, { "tag": "Electrochemistry", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Protein Conformation", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/2ATFCJUR" }, "dateAdded": "2011-09-27T09:18:09Z", "dateModified": "2011-09-27T09:18:09Z" } }, { "key": "PA7SWZ32", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/PA7SWZ32", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/PA7SWZ32", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Xu et al.", "parsedDate": "2008-09", "numChildren": 0 }, "data": { "key": "PA7SWZ32", "version": 1, "itemType": "journalArticle", "title": "Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics", "creators": [ { "creatorType": "author", "firstName": "Yechun", "lastName": "Xu" }, { "creatorType": "author", "firstName": "Jacques-Philippe", "lastName": "Colletier" }, { "creatorType": "author", "firstName": "Martin", "lastName": "Weik" }, { "creatorType": "author", "firstName": "Hualiang", "lastName": "Jiang" }, { "creatorType": "author", "firstName": "John", "lastName": "Moult" }, { "creatorType": "author", "firstName": "Israel", "lastName": "Silman" }, { "creatorType": "author", "firstName": "Joel L", "lastName": "Sussman" } ], "abstractNote": "The high aromatic content of the deep and narrow active-site gorge of acetylcholinesterase (AChE) is a remarkable feature of this enzyme. Here, we analyze conformational flexibility of the side chains of the 14 conserved aromatic residues in the active-site gorge of Torpedo californica AChE based on the 47 three-dimensional crystal structures available for the native enzyme, and for its complexes and conjugates, and on a 20-ns molecular dynamics (MD) trajectory of the native enzyme. The degree of flexibility of these 14 aromatic side chains is diverse. Although the side-chain conformations of F330 and W279 are both very flexible, the side-chain conformations of F120, W233, W432, Y70, Y121, F288, F290 and F331 appear to be fixed. Residues located on, or adjacent to, the Omega-loop (C67-C94), namely W84, Y130, Y442, and Y334, display different flexibilities in the MD simulations and in the crystal structures. An important outcome of our study is that the majority of the side-chain conformations observed in the 47 Torpedo californica AChE crystal structures are faithfully reproduced by the MD simulation on the native enzyme. Thus, the protein can assume these conformations even in the absence of the ligand that permitted their experimental detection. These observations are pertinent to structure-based drug design.", "publicationTitle": "Biophysical Journal", "publisher": "", "place": "", "date": "Sep 2008", "volume": "95", "issue": "5", "section": "", "partNumber": "", "partTitle": "", "pages": "2500-2511", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Biophys. J.", "DOI": "10.1529/biophysj.108.129601", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/18502801", "accessDate": "2011-09-27T08:46:03Z", "PMID": "", "PMCID": "", "ISSN": "1542-0086", "archive": "", "archiveLocation": "", "shortTitle": "Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 18502801", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Amino Acids, Aromatic", "type": 1 }, { "tag": "Animals", "type": 1 }, { "tag": "Binding Sites", "type": 1 }, { "tag": "Computer Simulation", "type": 1 }, { "tag": "Crystallography, X-Ray", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Protein Conformation", "type": 1 }, { "tag": "Torpedo", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/52WFTXJ9" }, "dateAdded": "2011-09-27T08:46:03Z", "dateModified": "2011-09-27T08:46:03Z" } }, { "key": "9XVTC3G3", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/9XVTC3G3", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/9XVTC3G3", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Axelsen et al.", "parsedDate": "1994-02", "numChildren": 0 }, "data": { "key": "9XVTC3G3", "version": 1, "itemType": "journalArticle", "title": "Structure and dynamics of the active site gorge of acetylcholinesterase: synergistic use of molecular dynamics simulation and X-ray crystallography", "creators": [ { "creatorType": "author", "firstName": "P H", "lastName": "Axelsen" }, { "creatorType": "author", "firstName": "M", "lastName": "Harel" }, { "creatorType": "author", "firstName": "I", "lastName": "Silman" }, { "creatorType": "author", "firstName": "J L", "lastName": "Sussman" } ], "abstractNote": "The active site of acetylcholinesterase (AChE) from Torpedo californica is located 20 A from the enzyme surface at the bottom of a narrow gorge. To understand the role of this gorge in the function of AChE, we have studied simulations of its molecular dynamics. When simulations were conducted with pure water filling the gorge, residues in the vicinity of the active site deviated quickly and markedly from the crystal structure. Further study of the original crystallographic data suggests that a bis-quaternary decamethonium (DECA) ion, acquired during enzyme purification, residues in the gorge. There is additional electron density within the gorge that may represent small bound cations. When DECA and 2 cations are placed within the gorge, the simulation and the crystal structure are dramatically reconciled. The small cations, more so than DECA, appear to stabilize part of the gorge wall through electrostatic interactions. This part of the gorge wall is relatively thin and may regulate substrate, product, and water movement through the active site.", "publicationTitle": "Protein Science: A Publication of the Protein Society", "publisher": "", "place": "", "date": "Feb 1994", "volume": "3", "issue": "2", "section": "", "partNumber": "", "partTitle": "", "pages": "188-197", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Protein Sci.", "DOI": "10.1002/pro.5560030204", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/8003956", "accessDate": "2011-09-27T08:45:39Z", "PMID": "", "PMCID": "", "ISSN": "0961-8368", "archive": "", "archiveLocation": "", "shortTitle": "Structure and dynamics of the active site gorge of acetylcholinesterase", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 8003956", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Animals", "type": 1 }, { "tag": "Binding Sites", "type": 1 }, { "tag": "Computer Simulation", "type": 1 }, { "tag": "Crystallization", "type": 1 }, { "tag": "Crystallography, X-Ray", "type": 1 }, { "tag": "Decamethonium Compounds", "type": 1 }, { "tag": "Electrochemistry", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Protein Structure, Secondary", "type": 1 }, { "tag": "Torpedo", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/CTIT3GDF" }, "dateAdded": "2011-09-27T08:45:39Z", "dateModified": "2011-09-27T08:45:39Z" } }, { "key": "Z36VZF5B", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/Z36VZF5B", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/Z36VZF5B", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Kuca et al.", "parsedDate": "2006-03", "numChildren": 0 }, "data": { "key": "Z36VZF5B", "version": 1, "itemType": "journalArticle", "title": "Structural requirements of acetylcholinesterase reactivators", "creators": [ { "creatorType": "author", "firstName": "Kamil", "lastName": "Kuca" }, { "creatorType": "author", "firstName": "Daniel", "lastName": "Juna" }, { "creatorType": "author", "firstName": "Kamil", "lastName": "Musilek" } ], "abstractNote": "Nerve agents (sarin, soman, cyclosarin, tabun and VX agent) and pesticides (paraoxon, chlorpyrifos, TEPP) represent extremely toxic group of organophosphorus compounds (OPCs). These compounds inhibit enzyme acetylcholinesterase (AChE, EC 3.1.1.7) via its phosphorylation or phosphonylation at the serine hydroxy group in its active site. Afterwards, AChE is not able to serve its physiological function and intoxicated organism is died due to overstimulation of cholinergic nervous system. The current standard treatment of poisoning with highly toxic OPCs usually consists of the combined administration of anticholinergic drugs (preferably atropine) and AChE reactivators (called \"oximes\"). Anticholinergic drugs block effects of accumulated neurotransmitter acetylcholine at nicotinic and muscarinic receptor sites, while oximes reactivate AChE inhibited by OPCs. Unfortunately, none from the currently used oximes is sufficiently effective against all known nerve agents and pesticides. Therefore, to find new oximes able to sufficiently reactivate inhibited AChE (regardless of the type of OPCs) is still very important task for medicinal chemistry with the aim to improve the efficacy of antidotal treatment of the acute poisonings mentioned. In this paper, the relationship between chemical structure of AChE reactivators and their ability to reactivate AChE inhibited by several nerve agents and pesticides is summarized. It is shown that there are several structural fragments possibly involving in the structure of proposed AChE reactivators. Finally, an attempt of a future course of new AChE reactivators development is discussed.", "publicationTitle": "Mini Reviews in Medicinal Chemistry", "publisher": "", "place": "", "date": "Mar 2006", "volume": "6", "issue": "3", "section": "", "partNumber": "", "partTitle": "", "pages": "269-277", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Mini Rev Med Chem", "DOI": "", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/16515465", "accessDate": "2011-09-27T08:44:54Z", "PMID": "", "PMCID": "", "ISSN": "1389-5575", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 16515465", "tags": [ { "tag": "Acetylcholine", "type": 1 }, { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Animals", "type": 1 }, { "tag": "Antidotes", "type": 1 }, { "tag": "Atropine", "type": 1 }, { "tag": "Binding Sites", "type": 1 }, { "tag": "Chemical Warfare Agents", "type": 1 }, { "tag": "Cholinesterase Inhibitors", "type": 1 }, { "tag": "Cholinesterase Reactivators", "type": 1 }, { "tag": "Enzyme Activation", "type": 1 }, { "tag": "Humans", "type": 1 }, { "tag": "Muscarinic Antagonists", "type": 1 }, { "tag": "Neurotransmitter Agents", "type": 1 }, { "tag": "Nicotine", "type": 1 }, { "tag": "Oximes", "type": 1 }, { "tag": "Phosphorylation", "type": 1 }, { "tag": "Receptor, Muscarinic M1", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/CVKT2ZHW" }, "dateAdded": "2011-09-27T08:44:54Z", "dateModified": "2011-09-27T08:44:54Z" } }, { "key": "NI9RP82I", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/NI9RP82I", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/NI9RP82I", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Garcia et al.", "parsedDate": "2010-09-06", "numChildren": 0 }, "data": { "key": "NI9RP82I", "version": 1, "itemType": "journalArticle", "title": "Novel oximes as blood-brain barrier penetrating cholinesterase reactivators", "creators": [ { "creatorType": "author", "firstName": "Gregory E", "lastName": "Garcia" }, { "creatorType": "author", "firstName": "Amy J", "lastName": "Campbell" }, { "creatorType": "author", "firstName": "John", "lastName": "Olson" }, { "creatorType": "author", "firstName": "Deborah", "lastName": "Moorad-Doctor" }, { "creatorType": "author", "firstName": "Venee I", "lastName": "Morthole" } ], "abstractNote": "The US Army utilizes pralidoxime (2-PAM) for the reactivation of OP-inhibited AChE. While 2-PAM effectively reactivates acetylcholinesterase (AChE) in the body, it does not cross the blood-brain barrier (BBB) at therapeutically relevant levels. To address this problem of central nervous system AChE reactivation, novel sugar-oxime conjugates were utilized. These 'sugar-oximes' would potentially be transported across the BBB because they contain a sugar moiety which would be recognized by the facilitative glucose transporters. Eight previously reported, but understudied sugar-oximes, as well as six novel sugar-oximes were synthesized, and their ability to reactivate both human red blood cell AChE and plasma butyrylcholinesterase poisoned with DFP, paraoxon, sarin and VX were tested. The results show that the novel sugar-oxime 13c was more active than the other compounds with a reactivation potential similar to 2-PAM. The sugar-oxime 8b had low toxicity with a LD(50) of 1,590 mg/kg from a single IM dose in the guinea pig and >2,000 mg/kg IP in the mouse. Histopathological analysis showed that there were no apparent differences in hippocampus, heart, liver, kidney sciatic nerve, or skeletal muscle between treated and untreated animals. These results show that sugar-oximes can be effective reactivators and suggest that high treatment doses may be possible.", "publicationTitle": "Chemico-Biological Interactions", "publisher": "", "place": "", "date": "Sep 6, 2010", "volume": "187", "issue": "1-3", "section": "", "partNumber": "", "partTitle": "", "pages": "199-206", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Chem. Biol. Interact.", "DOI": "10.1016/j.cbi.2010.02.033", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/20227398", "accessDate": "2011-09-27T08:44:41Z", "PMID": "", "PMCID": "", "ISSN": "1872-7786", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 20227398", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Animals", "type": 1 }, { "tag": "Blood-Brain Barrier", "type": 1 }, { "tag": "Butyrylcholinesterase", "type": 1 }, { "tag": "Carbohydrates", "type": 1 }, { "tag": "Cholinesterase Inhibitors", "type": 1 }, { "tag": "Cholinesterase Reactivators", "type": 1 }, { "tag": "Enzyme Activation", "type": 1 }, { "tag": "Guinea Pigs", "type": 1 }, { "tag": "Humans", "type": 1 }, { "tag": "Mice", "type": 1 }, { "tag": "Oximes", "type": 1 }, { "tag": "Phosphoric Acid Esters", "type": 1 }, { "tag": "Toxicity Tests", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/SMA8KZD9" }, "dateAdded": "2011-09-27T08:44:41Z", "dateModified": "2011-09-27T08:44:41Z" } }, { "key": "CTX6ARGT", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/CTX6ARGT", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/CTX6ARGT", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Ekström et al.", "parsedDate": "2006-08-28", "numChildren": 0 }, "data": { "key": "CTX6ARGT", "version": 1, "itemType": "journalArticle", "title": "Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime: structural basis for differences in the ability to reactivate tabun conjugates", "creators": [ { "creatorType": "author", "firstName": "Fredrik", "lastName": "Ekström" }, { "creatorType": "author", "firstName": "Yuan-Ping", "lastName": "Pang" }, { "creatorType": "author", "firstName": "Malin", "lastName": "Boman" }, { "creatorType": "author", "firstName": "Elisabet", "lastName": "Artursson" }, { "creatorType": "author", "firstName": "Christine", "lastName": "Akfur" }, { "creatorType": "author", "firstName": "Susanne", "lastName": "Börjegren" } ], "abstractNote": "Inhibition of acetylcholinesterase (AChE) by organophosphorus compounds (OPs) such as pesticides and nerve agents causes acute toxicity or death of the intoxicated individual. The inhibited AChE may be reactivated by certain oximes as antidotes for clinical treatment of OP-intoxications. Crystal structures of the oximes HI-6, Ortho-7 and obidoxime in complex with Mus musculus acetylcholinesterase (mAChE) reveal different roles of the peripheral anionic site (PAS) in the binding of the oximes. A limited structural change of the side chains of Trp286 and Asp74 facilitates the intercalation of the 4-carboxylamide pyridinium ring of HI-6 between the side chains of Tyr124 and Trp286. The 2-carboxyimino pyridinium ring of HI-6 is accommodated at the entrance of the catalytic site with the oximate forming a hydrogen bond to the main-chain nitrogen atom of Phe295. In contrast to HI-6, the coordination of Ortho-7 and obidoxime within the PAS is facilitated by an extended structural change of Trp286 that allows one of the carboxyimino pyridinium rings to form a cation-pi interaction with the aromatic groups of Tyr72 and Trp286. The central chain of Ortho-7 and obidoxime is loosely coordinated in the active-site gorge, whereas the second carboxyimino pyridinium ring is accommodated in the vicinity of the phenol ring of Tyr337. The structural data clearly show analogous coordination of Ortho-7 and obidoxime within the active-site gorge of AChE. Different ability to reactivate AChE inhibited by tabun is shown in end-point reactivation experiments where HI-6, Ortho-7 and obidoxime showed an efficiency of 1, 45 and 38%, respectively. The low efficiency of HI-6 and the significantly higher efficiency of Ortho-7 and obidoxime may be explained by the differential binding of the oximes in the PAS and active-site gorge of AChE.", "publicationTitle": "Biochemical Pharmacology", "publisher": "", "place": "", "date": "Aug 28, 2006", "volume": "72", "issue": "5", "section": "", "partNumber": "", "partTitle": "", "pages": "597-607", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Biochem. Pharmacol.", "DOI": "10.1016/j.bcp.2006.05.027", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/16876764", "accessDate": "2011-09-27T08:43:01Z", "PMID": "", "PMCID": "", "ISSN": "0006-2952", "archive": "", "archiveLocation": "", "shortTitle": "Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 16876764", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Chemical Warfare Agents", "type": 1 }, { "tag": "Cholinesterase Inhibitors", "type": 1 }, { "tag": "Crystallography, X-Ray", "type": 1 }, { "tag": "Hydrogen Bonding", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Nitrogen", "type": 1 }, { "tag": "Obidoxime Chloride", "type": 1 }, { "tag": "Oximes", "type": 1 }, { "tag": "Phosphoric Acid Esters", "type": 1 }, { "tag": "Protein Conformation", "type": 1 }, { "tag": "Pyridinium Compounds", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/4ZITQFVW" }, "dateAdded": "2011-09-27T08:43:01Z", "dateModified": "2011-09-27T08:43:01Z" } }, { "key": "QRKE3G9Q", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/QRKE3G9Q", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/QRKE3G9Q", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Bourne et al.", "parsedDate": "2003-01-02", "numChildren": 0 }, "data": { "key": "QRKE3G9Q", "version": 1, "itemType": "journalArticle", "title": "Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site", "creators": [ { "creatorType": "author", "firstName": "Yves", "lastName": "Bourne" }, { "creatorType": "author", "firstName": "Palmer", "lastName": "Taylor" }, { "creatorType": "author", "firstName": "Zoran", "lastName": "Radić" }, { "creatorType": "author", "firstName": "Pascale", "lastName": "Marchot" } ], "abstractNote": "The peripheral anionic site on acetylcholinesterase (AChE), located at the active center gorge entry, encompasses overlapping binding sites for allosteric activators and inhibitors; yet, the molecular mechanisms coupling this site to the active center at the gorge base to modulate catalysis remain unclear. The peripheral site has also been proposed to be involved in heterologous protein associations occurring during synaptogenesis or upon neurodegeneration. A novel crystal form of mouse AChE, combined with spectrophotometric analyses of the crystals, enabled us to solve unique structures of AChE with a free peripheral site, and as three complexes with peripheral site inhibitors: the phenylphenanthridinium ligands, decidium and propidium, and the pyrogallol ligand, gallamine, at 2.20-2.35 A resolution. Comparison with structures of AChE complexes with the peptide fasciculin or with organic bifunctional inhibitors unveils new structural determinants contributing to ligand interactions at the peripheral site, and permits a detailed topographic delineation of this site. Hence, these structures provide templates for designing compounds directed to the enzyme surface that modulate specific surface interactions controlling catalytic activity and non-catalytic heterologous protein associations.", "publicationTitle": "The EMBO Journal", "publisher": "", "place": "", "date": "Jan 2, 2003", "volume": "22", "issue": "1", "section": "", "partNumber": "", "partTitle": "", "pages": "1-12", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "EMBO J.", "DOI": "10.1093/emboj/cdg005", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/12505979", "accessDate": "2011-09-27T08:40:50Z", "PMID": "", "PMCID": "", "ISSN": "0261-4189", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 12505979", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Amino Acid Sequence", "type": 1 }, { "tag": "Animals", "type": 1 }, { "tag": "Binding Sites", "type": 1 }, { "tag": "Cell Line", "type": 1 }, { "tag": "Humans", "type": 1 }, { "tag": "Ligands", "type": 1 }, { "tag": "Macromolecular Substances", "type": 1 }, { "tag": "Mice", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Molecular Sequence Data", "type": 1 }, { "tag": "Protein Conformation", "type": 1 }, { "tag": "Recombinant Proteins", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/MG8G8ZCH" }, "dateAdded": "2011-09-27T08:40:50Z", "dateModified": "2011-09-27T08:40:50Z" } }, { "key": "DH5TDJE4", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/DH5TDJE4", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/DH5TDJE4", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Worek et al.", "parsedDate": "2004-12-01", "numChildren": 0 }, "data": { "key": "DH5TDJE4", "version": 1, "itemType": "journalArticle", "title": "Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes", "creators": [ { "creatorType": "author", "firstName": "Franz", "lastName": "Worek" }, { "creatorType": "author", "firstName": "Horst", "lastName": "Thiermann" }, { "creatorType": "author", "firstName": "Ladislaus", "lastName": "Szinicz" }, { "creatorType": "author", "firstName": "Peter", "lastName": "Eyer" } ], "abstractNote": "The wide-spread use of organophosphorus compounds (OP) as pesticides and the availability of highly toxic OP-type chemical warfare agents (nerve agents) underlines the necessity for an effective medical treatment. Acute OP toxicity is primarily caused by inhibition of acetylcholinesterase (AChE, EC 3.1.1.7). Reactivators (oximes) of inhibited AChE are a mainstay of treatment, however, the commercially available compounds, obidoxime and pralidoxime, are considered to be rather ineffective against various nerve agents. The antidotal efficacy of new oximes is primarily tested in animals for ethical reasons. However, the various interactions between AChE, OP and oximes can be investigated with human AChE which enables the direct assessment of oxime potency, thus excluding species differences. The kinetics of inhibition, reactivation and aging were investigated with human erythrocyte AChE, various structurally different OP (organophosphates, -phosphonates and phosphoramidates) and oximes (obidoxime, pralidoxime, HI 6, HLö 7). The inhibitory potency of OPs, reactivating potency of oximes and spontaneous reactivation and aging were strongly affected by the structural characteristics of the OPs and of the phosphyl-AChE-complex. The kinetic data emphasize the superior inhibitory potency of organophosphonates. AChE inhibited by various phosphoramidates was mostly resistant towards reactivation by oximes while phosphonylated AChE was easily reactivated. HLö 7 was most potent with phosphonylated AChE and obidoxime with AChE inhibited by organophosphates and phosphoramidates. With the exception of soman, OP-inhibited AChE aged rather slowly (t(1/2) 3-231 h) and reactivated spontaneously with some compounds. These results indicate that there is obviously no direct structure-activity relationship for the various interactions of human AChE, OPs and oximes.", "publicationTitle": "Biochemical Pharmacology", "publisher": "", "place": "", "date": "Dec 1, 2004", "volume": "68", "issue": "11", "section": "", "partNumber": "", "partTitle": "", "pages": "2237-2248", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Biochem. Pharmacol.", "DOI": "10.1016/j.bcp.2004.07.038", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/15498514", "accessDate": "2011-09-27T08:40:12Z", "PMID": "", "PMCID": "", "ISSN": "0006-2952", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 15498514", "tags": [ { "tag": "Acetylcholinesterase", "type": 1 }, { "tag": "Aging", "type": 1 }, { "tag": "Drug Interactions", "type": 1 }, { "tag": "Humans", "type": 1 }, { "tag": "Kinetics", "type": 1 }, { "tag": "Organophosphorus Compounds", "type": 1 }, { "tag": "Oximes", "type": 1 }, { "tag": "Structure-Activity Relationship", "type": 1 } ], "collections": [ "7MQGQTTS" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/SPGRK2TJ" }, "dateAdded": "2011-09-27T08:40:12Z", "dateModified": "2011-09-27T08:40:12Z" } }, { "key": "AVNUTAU7", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/AVNUTAU7", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/AVNUTAU7", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Felder et al.", "parsedDate": "1997-10", "numChildren": 0 }, "data": { "key": "AVNUTAU7", "version": 1, "itemType": "journalArticle", "title": "External and internal electrostatic potentials of cholinesterase models", "creators": [ { "creatorType": "author", "firstName": "C E", "lastName": "Felder" }, { "creatorType": "author", "firstName": "S A", "lastName": "Botti" }, { "creatorType": "author", "firstName": "S", "lastName": "Lifson" }, { "creatorType": "author", "firstName": "I", "lastName": "Silman" }, { "creatorType": "author", "firstName": "J L", "lastName": "Sussman" } ], "abstractNote": "The electrostatic potentials for the three-dimensional structures of cholinesterases from various species were calculated, using the Delphi algorithm, on the basis of the Poisson-Boltzmann equation. We used structures for Torpedo californica and mouse acetylcholinesterase, and built homology models of the human, Bungarus fasciatus, and Drosophila melanogaster acetylcholinesterases and human butyrylcholinesterase. All these structures reveal a negative external surface potential, in the area around the entrance to the active-site gorge, that becomes more negative as the rim of the gorge is approached. Moreover, in all cases, the potential becomes increasingly more negative along the central axis running down the gorge, and is largest at the base of the gorge, near the active site. Ten key acidic residues conserved in the sequence alignments of AChE from various species, both in the surface area near the entrance of the active-site gorge and at its base, appear to be primarily responsible for these potentials. The potentials are highly correlated among the structures examined, down to sequence identities as low as 35%. This indicates that they are a conserved property of the cholinesterase family, could serve to attract the positively charged substrate into and down the gorge to the active site, and may play other roles important for cholinesterase function.", "publicationTitle": "Journal of Molecular Graphics & Modelling", "publisher": "", "place": "", "date": "Oct 1997", "volume": "15", "issue": "5", "section": "", "partNumber": "", "partTitle": "", "pages": "318-327, 335-337", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "J. Mol. Graph. Model.", "DOI": "", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/9640563", "accessDate": "2011-09-26T07:52:38Z", "PMID": "", "PMCID": "", "ISSN": "1093-3263", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 9640563", "tags": [ { "tag": "Amino Acid Sequence", "type": 1 }, { "tag": "Animals", "type": 1 }, { "tag": "Binding Sites", "type": 1 }, { "tag": "Butyrylcholinesterase", "type": 1 }, { "tag": "Cholinesterases", "type": 1 }, { "tag": "Computer Simulation", "type": 1 }, { "tag": "Conserved Sequence", "type": 1 }, { "tag": "Humans", "type": 1 }, { "tag": "Mice", "type": 1 }, { "tag": "Models, Molecular", "type": 1 }, { "tag": "Molecular Sequence Data", "type": 1 }, { "tag": "Protein Conformation", "type": 1 }, { "tag": "Protein Folding", "type": 1 }, { "tag": "Sequence Homology, Amino Acid", "type": 1 }, { "tag": "Static Electricity", "type": 1 } ], "collections": [], "relations": {}, "dateAdded": "2011-09-26T07:52:38Z", "dateModified": "2011-09-26T07:52:38Z" } }, { "key": "T7V8R6KT", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/T7V8R6KT", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/T7V8R6KT", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Irwin and Shoichet", "parsedDate": "2005-02", "numChildren": 0 }, "data": { "key": "T7V8R6KT", "version": 1, "itemType": "journalArticle", "title": "ZINC--a free database of commercially available compounds for virtual screening", "creators": [ { "creatorType": "author", "firstName": "John J", "lastName": "Irwin" }, { "creatorType": "author", "firstName": "Brian K", "lastName": "Shoichet" } ], "abstractNote": "A critical barrier to entry into structure-based virtual screening is the lack of a suitable, easy to access database of purchasable compounds. We have therefore prepared a library of 727,842 molecules, each with 3D structure, using catalogs of compounds from vendors (the size of this library continues to grow). The molecules have been assigned biologically relevant protonation states and are annotated with properties such as molecular weight, calculated LogP, and number of rotatable bonds. Each molecule in the library contains vendor and purchasing information and is ready for docking using a number of popular docking programs. Within certain limits, the molecules are prepared in multiple protonation states and multiple tautomeric forms. In one format, multiple conformations are available for the molecules. This database is available for free download (http://zinc.docking.org) in several common file formats including SMILES, mol2, 3D SDF, and DOCK flexibase format. A Web-based query tool incorporating a molecular drawing interface enables the database to be searched and browsed and subsets to be created. Users can process their own molecules by uploading them to a server. Our hope is that this database will bring virtual screening libraries to a wide community of structural biologists and medicinal chemists.", "publicationTitle": "Journal of Chemical Information and Modeling", "publisher": "", "place": "", "date": "2005 Jan-Feb", "volume": "45", "issue": "1", "section": "", "partNumber": "", "partTitle": "", "pages": "177-182", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "J Chem Inf Model", "DOI": "10.1021/ci049714+", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/15667143", "accessDate": "2011-09-25T18:29:52Z", "PMID": "", "PMCID": "", "ISSN": "1549-9596", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 15667143", "tags": [ { "tag": "Databases, Factual", "type": 1 }, { "tag": "Drug Design", "type": 1 }, { "tag": "Libraries, Digital", "type": 1 }, { "tag": "Molecular Conformation", "type": 1 }, { "tag": "Molecular Structure", "type": 1 } ], "collections": [ "SW64SGCK" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/Z57N7JFJ" }, "dateAdded": "2011-09-25T18:29:52Z", "dateModified": "2011-09-25T18:29:52Z" } }, { "key": "Q4SE6ZCJ", "version": 1, "library": { "type": "group", "id": 48622, "name": "Tomingas Stanislav", "links": { "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/48622/items/Q4SE6ZCJ", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/tomingas_stanislav/items/Q4SE6ZCJ", "type": "text/html" } }, "meta": { "createdByUser": { "id": 652514, "username": "faulbeer", "name": "Stanislav Tomingas", "links": { "alternate": { "href": "https://www.zotero.org/faulbeer", "type": "text/html" } } }, "creatorSummary": "Laio and Parrinello", "parsedDate": "2002-10-01", "numChildren": 0 }, "data": { "key": "Q4SE6ZCJ", "version": 1, "itemType": "journalArticle", "title": "Escaping free-energy minima", "creators": [ { "creatorType": "author", "firstName": "Alessandro", "lastName": "Laio" }, { "creatorType": "author", "firstName": "Michele", "lastName": "Parrinello" } ], "abstractNote": "We introduce a powerful method for exploring the properties of the multidimensional free energy surfaces (FESs) of complex many-body systems by means of coarse-grained non-Markovian dynamics in the space defined by a few collective coordinates. A characteristic feature of these dynamics is the presence of a history-dependent potential term that, in time, fills the minima in the FES, allowing the efficient exploration and accurate determination of the FES as a function of the collective coordinates. We demonstrate the usefulness of this approach in the case of the dissociation of a NaCl molecule in water and in the study of the conformational changes of a dialanine in solution.", "publicationTitle": "Proceedings of the National Academy of Sciences of the United States of America", "publisher": "", "place": "", "date": "Oct 1, 2002", "volume": "99", "issue": "20", "section": "", "partNumber": "", "partTitle": "", "pages": "12562-12566", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Proc. Natl. Acad. Sci. U.S.A.", "DOI": "10.1073/pnas.202427399", "citationKey": "", "url": "http://www.ncbi.nlm.nih.gov/pubmed/12271136", "accessDate": "2011-09-25T18:17:36Z", "PMID": "", "PMCID": "", "ISSN": "0027-8424", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "NCBI PubMed", "callNumber": "", "rights": "", "extra": "PMID: 12271136", "tags": [ { "tag": "Alanine", "type": 1 }, { "tag": "Chemistry", "type": 1 }, { "tag": "Models, Statistical", "type": 1 }, { "tag": "Normal Distribution", "type": 1 }, { "tag": "Sodium Chloride", "type": 1 }, { "tag": "Thermodynamics", "type": 1 }, { "tag": "Water", "type": 1 } ], "collections": [ "SW64SGCK" ], "relations": { "owl:sameAs": "http://zotero.org/groups/3679/items/WMCGJGT2" }, "dateAdded": "2011-09-25T18:17:36Z", "dateModified": "2011-09-25T18:17:36Z" } } ]