Authors: A. Kovalenko
Affilation: National Institute for Nanotechnology, Canada
Pages: 440 - 443
Keywords: molecular theory of solvation, molecular dynamics, AMBER package, computer-aided drug design, binding affinity, chaperonin, prion proteins
We have coupled the statistical-mechanical, molecular theory of solvation (a.k.a. 3D-RISM-KH) with molecular dynamics (MD) simulation in the Amber molecular dynamics package to contract solvent degrees of freedom. This included a number of accelerating schemes with several cutoffs for the interaction potentials and correlation functions, an iterative guess for the 3D-RISM solutions, and extrapolating solvent-induced forces and applying them in large multi-time steps (up to 20 fs) to enable simulation of large biomolecules. The coupled MD/3D-RISM-KH method makes feasible modeling of biomolecular structures of practical interest and thus has tremendous potential for computer-aided drug design. It allows one to study processes on extremely long timescales, as the solvent dynamics is accounted for statistically-mechanically. It replaces the MM/GBSA or MM/PBSA post-processing suffering from the empirical treatment of non-polar contributions with the MM/3D-RISM-KH accurate evaluation of the solvation thermodynamics. It yields 3D maps of binding affinity at once without any phenomenological approximations. This presentation will introduce the new MD/3D-RISM-KH method and will show how it yields function-related properties for biomolecular systems as large and complex as a solvated chaperonin (GroEL) and predicts binding maps of prion proteins for development of novel inhibitors of prion protein conversion.