Dynamic Analysis of Backbone-Hydrogen-Bond Propensity for Protein Binding and Drug Design

Abstract

The three-dimensional shape of a protein recorded in the Protein Data Bank (PDB) provides valuable information regarding its structure and stability. However, such a static picture might be veiling relevant information regarding protein dynamics and function. In fact, backbone hydrogen bonds (BHBs), as main determinants of protein structure, constitute context-dependent noncovalent interactions. These interactions face different environments along the protein chain, particularly at protein binding sites which might present different hydration properties from that of other regions of the protein surface. Here we characterize the hydration and hydrophobicity of protein binding sites by molecular dynamics (MD) simulations, focusing particularly on their BHBs. We also carry out a time-averaged contact matrix study to reveal the existence of BHBs whose net persistence in time differs markedly from their corresponding PDB-reported state. Such interactions where the PDB fails.