title: p53 R175H hydrophobic patch and H-bond reorganization observed by MD simulation.
abstract: Molecular dynamics simulations probe the origins of aberrant functionality of R175H p53, which normally prevent tumorigenesis. This hotspot mutation exhibits loss of its essential zinc cofactor, aggregation, and activation of gain of function promoters, characteristics contributing to the loss of normal p53 activity. This study provided molecular level insight into the reorganization of the hydrogen bonding network and the formation of a hydrophobic patch on the surface of the protein. The hydrogen bonding network globally redistributes at the expense of the stability of the β-sandwich structure, and surface residues reorganize to expose a 250 Å(2) hydrophobic patch of residues covering approximately 2% of the solvent accessible surface. These changes could both stabilize the protein in the conformation exposing the patch to solvent to mediate the reported aggregation, and cause a destabilization in the area associated with DNA binding residues to affect the specificity. The development of the patch prior to loss of zinc indicates that stabilizing the patch quickly may prevent zinc loss. Considerations for rational design of small molecule therapeutics in light of the structural insight has been discussed and it suggest the positive ring around the hydrophobic patch and conserved residues may constitute a druggable site.
authors.affiliation: Department of Chemistry, Vassar College, 124 Raymond Ave, Poughkeepsie, NY, 12604.|Department of Chemistry, Hall-Atwater Laboratories, Wesleyan University, Middletown, CT, 06459.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Thayer
authors.affiliation: Department of Chemistry, Vassar College, 124 Raymond Ave, Poughkeepsie, NY, 12604.|Department of Chemistry, University of Notre Dame, Notre Dame, IN, 46556.
authors.forename: Taylor R
authors.initials: TR
authors.lastname: Quinn
mesh_terms: D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: cancer; molecular dynamics; p53; rational drug design