Classification of Water Molecules in Protein Binding Sites. Barillari, C., Taylor, J., Viner, R., & Essex, J. J.~Am.~Chem.~Soc., 129(9):2577--2587, 2007. abstract bibtex Abstract: Water molecules play a crucial role in mediating the interaction between a ligand and a macromolecular receptor. An understanding of the nature and role of each water molecule in the active site of a protein could greatly increase the efficiency of rational drug design approaches: if the propensity of a water molecule for displacement can be determined, then synthetic effort may be most profitably applied to the design of specific ligands with the displacement of this water molecule in mind. In this paper, a thermodynamic analysis of water molecules in the binding sites of six proteins, each complexed with a number of inhibitors, is presented. Two classes of water molecules were identified: those conserved and not displaced by any of the ligands, and those that are displaced by some ligands. The absolute binding free energies of 54 water molecules were calculated using the double decoupling method, with replica exchange thermodynamic integration in Monte Carlo simulations. It was found that conserved water molecules are on average more tightly bound than displaced water molecules. In addition, Bayesian statistics is used to calculate the probability that a particular water molecule may be displaced by an appropriately designed ligand, given the calculated binding free energy of the water molecule. This approach therefore allows the numerical assessment of whether or not a given water molecule should be targeted for displacement as part of a rational drug design strategy.
@article{Barillari:2007aa,
Abstract = {Abstract: Water molecules play a crucial role in mediating the interaction
between a ligand and a macromolecular receptor. An understanding
of the nature and role of each water molecule in the active site
of a protein could greatly increase the efficiency of rational drug
design approaches: if the propensity of a water molecule for displacement
can be determined, then synthetic effort may be most profitably applied
to the design of specific ligands with the displacement of this water
molecule in mind. In this paper, a thermodynamic analysis of water
molecules in the binding sites of six proteins, each complexed with
a number of inhibitors, is presented. Two classes of water molecules
were identified: those conserved and not displaced by any of the
ligands, and those that are displaced by some ligands. The absolute
binding free energies of 54 water molecules were calculated using
the double decoupling method, with replica exchange thermodynamic
integration in Monte Carlo simulations. It was found that conserved
water molecules are on average more tightly bound than displaced
water molecules. In addition, Bayesian statistics is used to calculate
the probability that a particular water molecule may be displaced
by an appropriately designed ligand, given the calculated binding
free energy of the water molecule. This approach therefore allows
the numerical assessment of whether or not a given water molecule
should be targeted for displacement as part of a rational drug design
strategy.},
Affiliation = {Contribution from the School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, U.K., and Syngenta, Jealott's Hill International Research Centre, Bracknell, RG42 6EY, U.K.},
Author = {Barillari, C. and Taylor, J. and Viner, R. and Essex, J.W.},
Date-Added = {2007-12-11 17:01:03 -0500},
Date-Modified = {2009-02-21 09:57:16 -0500},
Issn = {0002-7863},
Journal = {J.~Am.~Chem.~Soc.},
Keywords = {thermodynamic; monte carlo;},
Number = {9},
Owner = {rajarshi},
Pages = {2577--2587},
Timestamp = {2007.04.11},
Title = {Classification of Water Molecules in Protein Binding Sites},
Volume = {129},
Year = {2007},
Bdsk-File-1 = {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},
Bdsk-Url-1 = {http://dx.doi.org/10.1021/ja066980q}}
Downloads: 0
{"_id":"tqCG4tqphckRP5hdJ","bibbaseid":"barillari-taylor-viner-essex-classificationofwatermoleculesinproteinbindingsites-2007","downloads":0,"creationDate":"2016-02-18T13:03:35.951Z","title":"Classification of Water Molecules in Protein Binding Sites","author_short":["Barillari, C.","Taylor, J.","Viner, R.","Essex, J."],"year":2007,"bibtype":"article","biburl":"https://dl.dropboxusercontent.com/u/26998770/main.bib","bibdata":{"bibtype":"article","type":"article","abstract":"Abstract: Water molecules play a crucial role in mediating the interaction between a ligand and a macromolecular receptor. An understanding of the nature and role of each water molecule in the active site of a protein could greatly increase the efficiency of rational drug design approaches: if the propensity of a water molecule for displacement can be determined, then synthetic effort may be most profitably applied to the design of specific ligands with the displacement of this water molecule in mind. In this paper, a thermodynamic analysis of water molecules in the binding sites of six proteins, each complexed with a number of inhibitors, is presented. Two classes of water molecules were identified: those conserved and not displaced by any of the ligands, and those that are displaced by some ligands. The absolute binding free energies of 54 water molecules were calculated using the double decoupling method, with replica exchange thermodynamic integration in Monte Carlo simulations. It was found that conserved water molecules are on average more tightly bound than displaced water molecules. In addition, Bayesian statistics is used to calculate the probability that a particular water molecule may be displaced by an appropriately designed ligand, given the calculated binding free energy of the water molecule. This approach therefore allows the numerical assessment of whether or not a given water molecule should be targeted for displacement as part of a rational drug design strategy.","affiliation":"Contribution from the School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, U.K., and Syngenta, Jealott's Hill International Research Centre, Bracknell, RG42 6EY, U.K.","author":[{"propositions":[],"lastnames":["Barillari"],"firstnames":["C."],"suffixes":[]},{"propositions":[],"lastnames":["Taylor"],"firstnames":["J."],"suffixes":[]},{"propositions":[],"lastnames":["Viner"],"firstnames":["R."],"suffixes":[]},{"propositions":[],"lastnames":["Essex"],"firstnames":["J.W."],"suffixes":[]}],"date-added":"2007-12-11 17:01:03 -0500","date-modified":"2009-02-21 09:57:16 -0500","issn":"0002-7863","journal":"J.~Am.~Chem.~Soc.","keywords":"thermodynamic; monte carlo;","number":"9","owner":"rajarshi","pages":"2577--2587","timestamp":"2007.04.11","title":"Classification of Water Molecules in Protein Binding Sites","volume":"129","year":"2007","bdsk-file-1":"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","bdsk-url-1":"http://dx.doi.org/10.1021/ja066980q","bibtex":"@article{Barillari:2007aa,\n\tAbstract = {Abstract: Water molecules play a crucial role in mediating the interaction\n\tbetween a ligand and a macromolecular receptor. An understanding\n\tof the nature and role of each water molecule in the active site\n\tof a protein could greatly increase the efficiency of rational drug\n\tdesign approaches: if the propensity of a water molecule for displacement\n\tcan be determined, then synthetic effort may be most profitably applied\n\tto the design of specific ligands with the displacement of this water\n\tmolecule in mind. In this paper, a thermodynamic analysis of water\n\tmolecules in the binding sites of six proteins, each complexed with\n\ta number of inhibitors, is presented. Two classes of water molecules\n\twere identified: those conserved and not displaced by any of the\n\tligands, and those that are displaced by some ligands. The absolute\n\tbinding free energies of 54 water molecules were calculated using\n\tthe double decoupling method, with replica exchange thermodynamic\n\tintegration in Monte Carlo simulations. It was found that conserved\n\twater molecules are on average more tightly bound than displaced\n\twater molecules. In addition, Bayesian statistics is used to calculate\n\tthe probability that a particular water molecule may be displaced\n\tby an appropriately designed ligand, given the calculated binding\n\tfree energy of the water molecule. This approach therefore allows\n\tthe numerical assessment of whether or not a given water molecule\n\tshould be targeted for displacement as part of a rational drug design\n\tstrategy.},\n\tAffiliation = {Contribution from the School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, U.K., and Syngenta, Jealott's Hill International Research Centre, Bracknell, RG42 6EY, U.K.},\n\tAuthor = {Barillari, C. and Taylor, J. and Viner, R. and Essex, J.W.},\n\tDate-Added = {2007-12-11 17:01:03 -0500},\n\tDate-Modified = {2009-02-21 09:57:16 -0500},\n\tIssn = {0002-7863},\n\tJournal = {J.~Am.~Chem.~Soc.},\n\tKeywords = {thermodynamic; monte carlo;},\n\tNumber = {9},\n\tOwner = {rajarshi},\n\tPages = {2577--2587},\n\tTimestamp = {2007.04.11},\n\tTitle = {Classification of Water Molecules in Protein Binding Sites},\n\tVolume = {129},\n\tYear = {2007},\n\tBdsk-File-1 = {YnBsaXN0MDDUAQIDBAUIJidUJHRvcFgkb2JqZWN0c1gkdmVyc2lvblkkYXJjaGl2ZXLRBgdUcm9vdIABqAkKFRYXGyIjVSRudWxs0wsMDQ4RElpOUy5vYmplY3RzViRjbGFzc1dOUy5rZXlzog8QgASABoAHohMUgAKAA1lhbGlhc0RhdGFccmVsYXRpdmVQYXRo0hgMGRpXTlMuZGF0YU8RAW4AAAAAAW4AAgAAA212IAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAMU5bQNIKwAAABCNbQ1qYTA2Njk4MHEucGRmAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAEI7nxcWAMAAAAAAAAAAAAAIAAwAACSAAAAAAAAAAAAAAAAAAAAAIYXJ0aWNsZXMAEAAIAADFObNTAAAAEQAIAADFxcaAAAAAAQAQABCNbQAKTIAACkxpAAB8EwACADBtdiA6VXNlcnM6cmd1aGE6RG9jdW1lbnRzOmFydGljbGVzOmphMDY2OTgwcS5wZGYADgAcAA0AagBhADAANgA2ADkAOAAwAHEALgBwAGQAZgAPAAgAAwBtAHYAIAASACxVc2Vycy9yZ3VoYS9Eb2N1bWVudHMvYXJ0aWNsZXMvamEwNjY5ODBxLnBkZgATAAEvAAAVAAIADP//AACABdIcHR4fWCRjbGFzc2VzWiRjbGFzc25hbWWjHyAhXU5TTXV0YWJsZURhdGFWTlNEYXRhWE5TT2JqZWN0XxAmLi4vLi4vRG9jdW1lbnRzL2FydGljbGVzL2phMDY2OTgwcS5wZGbSHB0kJaIlIVxOU0RpY3Rpb25hcnkSAAGGoF8QD05TS2V5ZWRBcmNoaXZlcgAIABEAFgAfACgAMgA1ADoAPABFAEsAUgBdAGQAbABvAHEAcwB1AHgAegB8AIYAkwCYAKACEgIUAhkCIgItAjECPwJGAk8CeAJ9AoACjQKSAAAAAAAAAgEAAAAAAAAAKAAAAAAAAAAAAAAAAAAAAqQ=},\n\tBdsk-Url-1 = {http://dx.doi.org/10.1021/ja066980q}}\n\n","author_short":["Barillari, C.","Taylor, J.","Viner, R.","Essex, J."],"key":"Barillari:2007aa","id":"Barillari:2007aa","bibbaseid":"barillari-taylor-viner-essex-classificationofwatermoleculesinproteinbindingsites-2007","role":"author","urls":{},"keyword":["thermodynamic; monte carlo;"],"downloads":0},"search_terms":["classification","water","molecules","protein","binding","sites","barillari","taylor","viner","essex"],"keywords":["thermodynamic; monte carlo;"],"authorIDs":[],"dataSources":["c5japf9eAQRaeMS4h"]}