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Thermodynamics of buried water clusters at a protein-ligand binding interface.
J Phys Chem B 2006; 110(3):1464-75JP

Abstract

The structure of the complex of cyclophilin A (CypA) with cyclosporin A (CsA, 1) shows a cluster of four water molecules buried at the binding interface, which is rearranged when CsA is replaced by (5-hydroxynorvaline)-2-cyclosporin (2). The thermodynamic contributions of each bound water molecule in the two complexes are explored with the inhomogeneous fluid solvation theory and molecular dynamics simulations. Water (WTR) 133 in complex 1 contributes little to the binding affinity, while WTR6 and 7 in complex 2 play an essential role in mediating protein-ligand binding with a hydrogen bond network. The calculations reveal that the rearrangement of the water molecules contributes favorably to the binding affinity, even though one of them is displaced going from ligand 1 to 2. Another favorable contribution comes from the larger protein-ligand interactions of ligand 2. However, these favorable contributions are not sufficient to overcome the unfavorable desolvation free energy change and the conformational entropy of the hydroxylpropyl group of ligand 2 in the complex, leading to a lower binding affinity of ligand 2. These physical insights may be useful in the development of improved scoring functions for binding affinity prediction.

Authors+Show Affiliations

Department of Chemistry, City College of New York/CUNY, Convent Ave & 138th Street, New York, New York 10031, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

16471698

Citation

Li, Zheng, and Themis Lazaridis. "Thermodynamics of Buried Water Clusters at a Protein-ligand Binding Interface." The Journal of Physical Chemistry. B, vol. 110, no. 3, 2006, pp. 1464-75.
Li Z, Lazaridis T. Thermodynamics of buried water clusters at a protein-ligand binding interface. J Phys Chem B. 2006;110(3):1464-75.
Li, Z., & Lazaridis, T. (2006). Thermodynamics of buried water clusters at a protein-ligand binding interface. The Journal of Physical Chemistry. B, 110(3), pp. 1464-75.
Li Z, Lazaridis T. Thermodynamics of Buried Water Clusters at a Protein-ligand Binding Interface. J Phys Chem B. 2006 Jan 26;110(3):1464-75. PubMed PMID: 16471698.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thermodynamics of buried water clusters at a protein-ligand binding interface. AU - Li,Zheng, AU - Lazaridis,Themis, PY - 2006/2/14/pubmed PY - 2006/8/30/medline PY - 2006/2/14/entrez SP - 1464 EP - 75 JF - The journal of physical chemistry. B JO - J Phys Chem B VL - 110 IS - 3 N2 - The structure of the complex of cyclophilin A (CypA) with cyclosporin A (CsA, 1) shows a cluster of four water molecules buried at the binding interface, which is rearranged when CsA is replaced by (5-hydroxynorvaline)-2-cyclosporin (2). The thermodynamic contributions of each bound water molecule in the two complexes are explored with the inhomogeneous fluid solvation theory and molecular dynamics simulations. Water (WTR) 133 in complex 1 contributes little to the binding affinity, while WTR6 and 7 in complex 2 play an essential role in mediating protein-ligand binding with a hydrogen bond network. The calculations reveal that the rearrangement of the water molecules contributes favorably to the binding affinity, even though one of them is displaced going from ligand 1 to 2. Another favorable contribution comes from the larger protein-ligand interactions of ligand 2. However, these favorable contributions are not sufficient to overcome the unfavorable desolvation free energy change and the conformational entropy of the hydroxylpropyl group of ligand 2 in the complex, leading to a lower binding affinity of ligand 2. These physical insights may be useful in the development of improved scoring functions for binding affinity prediction. SN - 1520-6106 UR - https://www.unboundmedicine.com/medline/citation/16471698/Thermodynamics_of_buried_water_clusters_at_a_protein_ligand_binding_interface_ L2 - https://dx.doi.org/10.1021/jp056020a DB - PRIME DP - Unbound Medicine ER -