PROTEIN-LIGAND STRUCTURE AND BINDING FREE ENERGY PREDICTION USING MOLECULAR DY- NAMICS IN MIXED SOLVENT

MODENUTTI, CARLOS P. ; BARRIL, XAVIER; ARCON, JUAN PABLO; LOPEZ, ELIAS D.; DEFELIPE, LUCAS A.; TURJANSKI, ADRIÁN G.; ALVAREZ-GARCIA, DANIEL; MARTI, MARCELO A.

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Small water miscible molecules (or cosolvents), that mimic spe-cific types of ligand molecular interactions, have been proven usefulto reveal protein−ligand interaction hotspots and thus are a relevantsource of information for drug development projects. In the pres-ent work we performed molecular dynamics simulations in mixedsolvents for 18 different proteins to determine solvent sites, i.e.space regions adjacent to the protein surface where the probabilityof finding a probe solvent atom is higher than that in the bulk sol-vent. The solvents used were water mixtures of ethanol, acetamide,acetonitrile and methylammonium acetate, as well as pure water.When analyzing the probe capacity to reveal known protein-ligandinteractions, results showed remarkable sensitivity for water (0.64)and specificity for ethanol-OH (0.56). These values were further im-proved when we only considered the ligand-based pharmacophoricpoints (0.73 and 0.61, respectively). Hydrophobic probes, such asmethyl ends of ethanol and acetonitrile, also displayed great perfor-mance. Therefore, ethanol specificity makes it a great probe to useas a pharmacophoric bias in docking experiments, with ethanol−OHsites guiding the position of ligand groups with hydrogen bondingcapabilities and ethanol-CH 3 sites guiding the location of ligand aro-matic hydrophobic rings. Biased redocking and cross docking exper-iments showed 70% vs. 20% success when compared with the con-ventional docking method. Furthermore, for targets extracted fromthe DUD-E data set, ligand enrichment factors were also increased(e.g. EF1% from 2.1% to 14.6% for AmpC β-lactamase). Finally, ac-curate predictions of binding free energies were obtained by addingthe ∆G contribution of solvent sites replaced by crystallized ligandgroups capable of establishing the same type of interactions. Theseresults highlight the relevancy of the method as a tool for protein-li-gand binding studies.