INVESTIGADORES
APPIGNANESI Gustavo Adrian
capítulos de libros
Título:
Dynamic Analysis of Backbone-Hydrogen-Bond Propensity for Protein Binding and Drug Design
Autor/es:
C.A. MENÉNDEZ; ACCORDINO, SEBASTIÁN R.; J. A. RODRÍGUEZ FIRS; GERBINO, DARÍO C.; APPIGNANESI, GUSTAVO A.
Libro:
Biopolymers for Medical Applications
Editorial:
CRC Press
Referencias:
Lugar: New York; Año: 2016; p. 317 - 338
Resumen:
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 picturemight be veiling relevant information regarding protein dynamics and function. Infact, backbone hydrogen bonds (BHBs), as main determinants of protein structure,constitute context-dependent non-covalent interactions. These interactions facedifferent environments along the protein chain, particularly at protein binding siteswhich might present different hydration properties from that of other regions of theprotein surface. Here we characterize the hydration and hydrophobicity of proteinbinding sites by molecular dynamics (MD) simulations, focusing particularly on theirBHBs. We also carry out a time-averaged contact matrix study to reveal the existenceof BHBs whose net persistence in time differs markedly from their correspondingPDB-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 bondingpropensity in solution. Additionally, such CBHBs are not found to be homogeneously distributed but to present a clear population enhancement at protein binding sites. Wealso relate them to local water exposure and analyze their behavior as ligand/drugtargets. In fact, we fi nd that when the apo protein forms its complex with its naturalprotein partner most of the CBHBs are quenched. A similar behavior is found whenthe apo protein binds a disruptive drug or ligand, albeit in a less optimal fashion insome cases. Thus, the dynamic analysis of hydrogen-bond propensity might lay thefoundations for new tools of interest in protein binding-site prediction and in leadoptimization for drug design.