INVESTIGADORES
GERBINO dario Cesar
capítulos de libros
Título:
Dynamic Analysis of Backbone-Hydrogen-Bond Propensity for Protein Binding and Drug Design
Autor/es:
CINTIA A. MENÉNDEZ; SEBASTIÁN R. ACCORDINO; ARIEL RODRIGUEZ FRIS; DARÍO C. GERBINO; GUSTAVO A. APPIGNANESI
Libro:
Biopolymers for Medical Applications
Editorial:
CRC Press Taylor and Francis Group
Referencias:
Lugar: Boca Raton, Florida; Año: 2016; p. 317 - 338
Resumen:
The Protein Data Bank (PDB) recorded structure of a protein gives us valuableinformation 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 non-covalent 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 to predict their dynamicalbehavior will be termed as ?chameleonic? BHBs (CBHBs), precisely to account fortheir tendency to change the structural prescription of the PDB for the opposite bonding propensity in solution. Additionally, such CBHBs are not found to be homogeneously distributed but to present a clear population enhancement at protein binding sites. We also relate them to local water exposure and analyze their behavior as ligand/drug targets. In fact, we fi nd that when the apo protein forms its complex with its natural protein partner most of the CBHBs are quenched. A similar behavior is found when the apo protein binds a disruptive drug or ligand, albeit in a less optimal fashion in some cases. Thus, the dynamic analysis of hydrogen-bond propensity might lay the foundations for new tools of interest in protein binding-site prediction and in lead optimization for drug design.