Thermodynamics of water at biomolecular interfaces.
Item
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Title
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Thermodynamics of water at biomolecular interfaces.
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Identifier
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AAI3231976
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identifier
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3231976
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Creator
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Li, Zheng.
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Contributor
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Adviser: Themis Lazaridis
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Date
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2006
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Language
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English
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Publisher
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City University of New York.
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Subject
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Chemistry, Physical | Chemistry, Biochemistry
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Abstract
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Water molecules are often found at the binding interface of biomolecular complexes mediating the interaction between polar groups or simply filling space. Recent experimental or theoretical studies have demonstrated the importance of taking such water molecules into account in considering the thermodynamic parameter changes in complex formation. In my doctoral research studies, we calculated the different thermodynamic contributions of such water molecules in several complexes and discussed whether the displacement of water molecule would be favorable in ligand design. We calculated the contribution of the strongly bound water molecules at the interface of three complexes (HIV-1 protease-KNI 272, Concanavalin A-trimannoside 1 and Cyclophilin A-Cyclosporin A and analog) to the thermodynamic properties using statistical mechanical formulas for the energy and entropy. The requisite correlation functions were obtained by molecular dynamics simulations. We find that the entropic penalty of ordering is usually large but is outweighed by the favorable water-protein interactions. We also find large negative contributions from some of these water molecules to the heat capacity. We also considered the thermodynamic consequences of displacement of the bound water molecule by ligand modification, including ligand desolvation, ligand conformational entropy loss and protein-ligand interactions. Our approach could be useful in rational drug design by estimating which bound water molecules would be most favorable to displace, which might be also helpful in the improvement of scoring function in predicting the protein-ligand binding affinity by incorporating the contributions from bound water.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
