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.