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Heterogeneous Hydration of p53/MDM2 Complex.

Guo Z, Li B, Dzubiella J, Cheng LT, McCammon JA, Che J - J Chem Theory Comput (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.

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.

No MeSH data available.


(A) Cross-section of water density profilethrough the bindingpocket based on the MD simulation at interdomain distance d = 12 Å. The molecular surface is represented withthe same color code as Figure 1 (Blue for hydrophobicresidues, red for charged residues, pink for neutral hydrophilic residues).The colors in the legend represent the average water density (rangefrom 0 to 2 and in units of bulk density ρ0). (B)The same cross-section water density profile as (A) without showingthe protein.
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fig3: (A) Cross-section of water density profilethrough the bindingpocket based on the MD simulation at interdomain distance d = 12 Å. The molecular surface is represented withthe same color code as Figure 1 (Blue for hydrophobicresidues, red for charged residues, pink for neutral hydrophilic residues).The colors in the legend represent the average water density (rangefrom 0 to 2 and in units of bulk density ρ0). (B)The same cross-section water density profile as (A) without showingthe protein.

Mentions: The waterdensity profile is constructed from a 40 ns MD simulation with TIP3Pwater. Figure 3 shows the cross-section ofwater density profile across the target protein MDM2 binding pocketwhen interdomain distance d = 12 Å. In thisfigure, the protein complex is represented by its molecular surfacewith the same color code as Figure 1. The valueof the local water density is represented by colors in the legend.White color indicates zero density, blue represents half of the bulkwater density, yellow represents the bulk water density, and red representstwice of the bulk water density.


Heterogeneous Hydration of p53/MDM2 Complex.

Guo Z, Li B, Dzubiella J, Cheng LT, McCammon JA, Che J - J Chem Theory Comput (2014)

(A) Cross-section of water density profilethrough the bindingpocket based on the MD simulation at interdomain distance d = 12 Å. The molecular surface is represented withthe same color code as Figure 1 (Blue for hydrophobicresidues, red for charged residues, pink for neutral hydrophilic residues).The colors in the legend represent the average water density (rangefrom 0 to 2 and in units of bulk density ρ0). (B)The same cross-section water density profile as (A) without showingthe protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3958133&req=5

fig3: (A) Cross-section of water density profilethrough the bindingpocket based on the MD simulation at interdomain distance d = 12 Å. The molecular surface is represented withthe same color code as Figure 1 (Blue for hydrophobicresidues, red for charged residues, pink for neutral hydrophilic residues).The colors in the legend represent the average water density (rangefrom 0 to 2 and in units of bulk density ρ0). (B)The same cross-section water density profile as (A) without showingthe protein.
Mentions: The waterdensity profile is constructed from a 40 ns MD simulation with TIP3Pwater. Figure 3 shows the cross-section ofwater density profile across the target protein MDM2 binding pocketwhen interdomain distance d = 12 Å. In thisfigure, the protein complex is represented by its molecular surfacewith the same color code as Figure 1. The valueof the local water density is represented by colors in the legend.White color indicates zero density, blue represents half of the bulkwater density, yellow represents the bulk water density, and red representstwice of the bulk water density.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.

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.

No MeSH data available.