Docking on protein that bind hydrophilic ligand: Incorporation of solvation structure from MD and statistical analysis in Autodock

DIEGO F. GAUTO, CARLOS M.A. GUARDIA, SANTIAGO DI LELLA, DARIO A. ESTRIN, MARCELO A. MARTI

Salta

Congreso; 3rd Latin American Protein Society Meeting. Salta, Argentina from October 13th to 16th, 2010; 2010

Docking on protein that bind hydrophilic ligand: Incorporation of solvation structure from MD and statistical analysis in Autodock Diego F. Gauto1, Carlos M.A. Guardia1, Santiago Di Lella1, Dario A. Estrin1, Marcelo A. Marti1,2 1Departamento de Química Inorgánica, Analítica, y Química Física INQUIMAE-CONICET y 2 Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II C1428EHA, Buenos Aires, Argentina. * e-mail: dgauto@qi.fcen.uba.ar During the process of protein-ligand complex formation, significant solvent reorganization is produced along the contact surface and many water molecules strongly bound to the protein’s ligand binding site must be displaced. Previous works from our group (1, 2), combining MD simulations with statistical mechanics analysis, showed that properties of the water molecules bound to the surface on the carbohydrate recognition sites (CRD) of various Lectins, resembles the structure of the Lectin-carbohydrate complex. Specifically, we defined so called water sites (WS) as space regions close to the protein surface with higher than bulk solvent water finding probability, and computed several thermodynamic and structural properties for them. Our results show that the probability of finding water molecules inside the WS is directly correlated to the likeliness of finding an hydroxyl group of the ligand in the protein-ligand complex. In the present work we propose to use this information for predicting protein-carbohydrate complexes structure. For this sake we added to commonly used molecular docking program Autodock, an additional potential based on the WS properties, which favors superposition of carbohydrate ligand OH group in the WS region. Using this methodology, we found a significant improvement on the efficiency of the program to find the correct position of the ligand with respect the crystallographic structure for several Lectin-carbohydrate complexes. References: 1. Di Lella, S., Marti, M. A., Alvarez, R. M. S., Estrin, D. A. & Díaz Ricci, J. C. J Phys Chem B 111, 7360-7366 (2007). 2. Gauto, D. F., Di Lella, S., Guardia, C. M., Estrin, D. A. & Marti, M. A. J Phys Chem B 113, 8717-24 (2009).