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Heterogeneous Hydration of p53/MDM2 Complex

[Image: see text] Water-mediated interactions play critical roles in biomolecular recognition processes. Explicit solvent molecular dynamics (MD) simulations and the variational implicit-solvent model (VISM) are used to study those hydration properties during binding for the biologically important p...

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Autores principales: Guo, Zuojun, Li, Bo, Dzubiella, Joachim, Cheng, Li-Tien, McCammon, J. Andrew, Che, Jianwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958133/
https://www.ncbi.nlm.nih.gov/pubmed/24803860
http://dx.doi.org/10.1021/ct400967m
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author Guo, Zuojun
Li, Bo
Dzubiella, Joachim
Cheng, Li-Tien
McCammon, J. Andrew
Che, Jianwei
author_facet Guo, Zuojun
Li, Bo
Dzubiella, Joachim
Cheng, Li-Tien
McCammon, J. Andrew
Che, Jianwei
author_sort Guo, Zuojun
collection PubMed
description [Image: see text] Water-mediated interactions play critical roles in biomolecular recognition processes. Explicit solvent molecular dynamics (MD) simulations and the variational implicit-solvent model (VISM) are used to study those hydration properties during binding for the biologically important p53/MDM2 complex. Unlike simple model solutes, in such a realistic and heterogeneous solute–solvent system with both geometrical and chemical complexity, the local water distribution sensitively depends on nearby amino acid properties and the geometric shape of the protein. We show that the VISM can accurately describe the locations of high and low density solvation shells identified by the MD simulations and can explain them by a local coupling balance of solvent–solute interaction potentials and curvature. In particular, capillary transitions between local dry and wet hydration states in the binding pocket are captured for interdomain distance between 4 to 6 Å, right at the onset of binding. The underlying physical connection between geometry and polarity is illustrated and quantified. Our study offers a microscopic and physical insight into the heterogeneous hydration behavior of the biologically highly relevant p53/MDM2 system and demonstrates the fundamental importance of hydrophobic effects for biological binding processes. We hope our study can help to establish new design rules for drugs and medical substances.
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spelling pubmed-39581332015-01-31 Heterogeneous Hydration of p53/MDM2 Complex Guo, Zuojun Li, Bo Dzubiella, Joachim Cheng, Li-Tien McCammon, J. Andrew Che, Jianwei J Chem Theory Comput [Image: see text] Water-mediated interactions play critical roles in biomolecular recognition processes. Explicit solvent molecular dynamics (MD) simulations and the variational implicit-solvent model (VISM) are used to study those hydration properties during binding for the biologically important p53/MDM2 complex. Unlike simple model solutes, in such a realistic and heterogeneous solute–solvent system with both geometrical and chemical complexity, the local water distribution sensitively depends on nearby amino acid properties and the geometric shape of the protein. We show that the VISM can accurately describe the locations of high and low density solvation shells identified by the MD simulations and can explain them by a local coupling balance of solvent–solute interaction potentials and curvature. In particular, capillary transitions between local dry and wet hydration states in the binding pocket are captured for interdomain distance between 4 to 6 Å, right at the onset of binding. The underlying physical connection between geometry and polarity is illustrated and quantified. Our study offers a microscopic and physical insight into the heterogeneous hydration behavior of the biologically highly relevant p53/MDM2 system and demonstrates the fundamental importance of hydrophobic effects for biological binding processes. We hope our study can help to establish new design rules for drugs and medical substances. American Chemical Society 2014-01-31 2014-03-11 /pmc/articles/PMC3958133/ /pubmed/24803860 http://dx.doi.org/10.1021/ct400967m Text en Copyright © 2014 American Chemical Society
spellingShingle Guo, Zuojun
Li, Bo
Dzubiella, Joachim
Cheng, Li-Tien
McCammon, J. Andrew
Che, Jianwei
Heterogeneous Hydration of p53/MDM2 Complex
title Heterogeneous Hydration of p53/MDM2 Complex
title_full Heterogeneous Hydration of p53/MDM2 Complex
title_fullStr Heterogeneous Hydration of p53/MDM2 Complex
title_full_unstemmed Heterogeneous Hydration of p53/MDM2 Complex
title_short Heterogeneous Hydration of p53/MDM2 Complex
title_sort heterogeneous hydration of p53/mdm2 complex
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958133/
https://www.ncbi.nlm.nih.gov/pubmed/24803860
http://dx.doi.org/10.1021/ct400967m
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