Solvent structure improves docking prediction in lectin carbohydrate complexes

DIEGO F GAUTO; ARIEL A PETRUK; CARLOS MODENUTTI; JUAN BLANCO; SANTIAGO DI LELLA; MARCELO A MARTI

GLYCOBIOLOGY

OXFORD UNIV PRESS INC

Lugar: Oxford; Año: 2012

0959-6658

<!-- @page { margin: 0.79in } P { margin-bottom: 0.14in; direction: ltr; color: #000000; text-align: center; widows: 2; orphans: 2 } P.western { font-family: "Times", "Times New Roman", serif; font-size: 20pt; so-language: en-US; font-weight: bold } P.cjk { font-family: "Times New Roman", serif; font-size: 20pt; so-language: zh-CN; font-weight: bold } P.ctl { font-family: "Times", "Times New Roman", serif; font-size: 10pt; so-language: ar-SA } A:link { color: #0000ff } A:visited { color: #800080 } A.western:visited { so-language: en-US } A.cjk:visited { so-language: zh-CN } A.ctl:visited { so-language: hi-IN } --> Recognition and complex formation between protein and carbohydrates is a key issue for many important biological processes. Determination of the three-dimensional structure of such complexes is thus most relevant, but particularly challenging due to their usually low binding affinity. In-silico docking methods have a long standing tradition in predicting protein-ligand complexes, and allow the potentially fast exploration of a number of possible protein-carbohydrate complex structures. However, determining which of these predicted complexes represents the correct structure is not a always straightforward. In this work, we present a modification of the scoring function provided by AutoDock4, a widely used docking software, based on the analysis of the solvent structure adjacent to the protein surface, as derived from Molecular Dynamics simulations, that allows the definition and characterization of regions with higher water occupancy than the bulk solvent, called water sites. They mimic the interaction held between the carbohydrate -OH groups and the protein. We used this information for an improved docking method in relation to its capacity to correctly predict the protein-carbohydrate complexes for a number of tested proteins, whose ligands range from the mono- to the tetrasaccharide size. Our results show that the presented method significantly improves the docking predictions. The resulting solvent-structure-biased docking protocol therefore appears as a powerful tool for the design and optimization of glycomimetic drugs development, while providing a new insight for the basic understanding of protein carbohydrate interactions. Moreover, the achieved improvement also underscores the relevance of the solvent structure for the protein carbohydrate recognition process.