title: Heterogeneous Hydration of p53/MDM2 Complex.
abstract: 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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Zuojun
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Mathematics and Center for Theoretical Biological Physics, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093-0112, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Physics, Humboldt University of Berlin , Newtonstr. 15, 12489 Berlin, Germany ; Soft Matter and Functional Materials, Helmholtz-Zentrum Berlin , Hahn-Meitner Platz 1, 14109 Berlin, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Dzubiella
authors.affiliation: Department of Mathematics, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093-0112, United States.
authors.forename: Li-Tien
authors.initials: LT
authors.lastname: Cheng
authors.affiliation: Department of Chemistry and Biochemistry, Department of Pharmacology, Howard Hughes Medical Institute, and Center for Theoretical Biological Physics, University of California , San Diego, 9500 Gilman Drive, La Jolla, California 92093-0365, United States.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Che