INQUIMAE   12526
INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
1. Glycobioinformatics: Using solvent structure to predict and characterize protein carbohydrate complexes
Autor/es:
MARCELO A. MARTI
Reunión:
Congreso; 1. 3er Congreso de la Asociacion Argentina de Bioinformatica y Biologia Computacional (A2B2C).; 2012
Resumen:
<!--
@page { margin: 0.79in }
P { margin-bottom: 0.08in }
-->
Formation
of protein ligand complexes is a fundamental process in biochemistry.
In-silico based methods that predict the structure of complexes, or
docking methods, are widely used and are an essential part of many
rational drug development programs. The potential and reliability of
any docking method lies in its capability to correctly predict the
complex structure, taking as starting point the structures of the
protein and ligand separately. Nevertheless, given the approximations
involved in the theoretical developments employed, results are not
always successfully achieved.
Carbohydrate
binding proteins are a large and diverse group of biomolecules
displaying a wide variety of biological activities including cell
recognition, communication and cell growth. In this context
understanding protein-carbohydrate interactions at the molecular
level with atomic resolution, is of fundamental importance for basic
and applied glycobiology. A common, but usually overlooked feature of
carbohydrates is the fact that their polar OH groups, quite
frequently bind to hydrophilic patches of the protein surface,
resulting in significant solvent displacement and reorganization.
Water molecules and carbohydrate OH groups can participate in similar
hydrogen binding networks when establishing contacts with protein
surfaces. With this in mind, we though to use this information in
order to in-silico predict the protein-carbohydrate complexes, with
higher accuracy than conventional docking methods.
Analyzing
the solvent structure at the protein surface is not an easy task. One
of the most potent methods for studying solvent structure is based on
the inhomogeneous fluid solvation theory (IFST) which allows the
determination of several properties for the water molecules from a
plain Molecular Dynamics (MD) simulation. Using, this methodology,
recently, we were able to show that solvent structure and dynamics at
protein surfaces involved in carbohydrate binding proteins are very
different as those from the bulk solvent, allowing the identification
of the so called water sites (WS) or hydration sites. The WS
correspond to definite regions in the area adjacent to the protein
surface where the probability of finding a water molecule is
significantly higher than that observed in the bulk solvent, and can
be further thermodynamically characterized using the IFST.
In
the present work, we used the characterization of the WS in the CBS
of several carbohydrate binding proteins, to modify the scoring
function of the Docking program Autodock in order to perform the
in-silico determination of the corresponding protein-ligand
complexes. Our results clearly show that the modified function
significantly improves the quality and accuracy of the results, both
in terms of how close the predicted complex structure resembles the
real one (i.e the one obtained by crystallography), and in the
differentiation of true from false positives and negatives. The
resulting solvent structure biased docking protocol thus results in a
powerful tool to the design and optimization of glycomimetic drugs
development, and for the basic understanding of protein carbohydrate
interactions.