Research & Publications
The research focuses on the application of computational methods to solve problems concerning structure and reactivity for biomolecular systems. This includes development and application of procedures for accurate calculation of protein-ligand binding affinities. Three approaches are taken that include explicit representation of the protein-ligand complexes using molecular mechanics (MM): a scoring function approach with the BOMB program, and extended linear response and free energy perturbation calculations using Monte Carlo sampling with explicit solvent. Recent examples addressed the binding of drug candidates to HIV-1 RT, factor Xa, COX-2, FAAH, and kinases. BOMB is also used for de novo drug design through the creation and screening of large combinatorial libraries. Modeling of reactions in gas phase, in solution and in enzymes is also studied. The aim is elucidation of reaction mechanisms and the origin of medium effects on rates. A QM/MM approach is taken, and the reacting systems are described with the improved semiempirical MO method PDDG/PM3 that we have developed. The enzymes and solvent are represented using MM, and the sampling is performed with Monte Carlo statistical mechanics. Our research group also has a leadership position in the development of force fields for water, organic and biomolecular systems and software for molecular modeling and drug design.