Leap-dynamics: efficient sampling of conformational space of proteins and peptides in solution

A molecular simulation scheme, called Leap-dynamics, that provides efficien t sampling of protein conformational space in solution is presented. The sc heme is a combined approach using a fast sampling method, imposing conforma tional 'leaps' to force the system over energy barriers, and molecular dyna mics (MD) for refinement. The presence of solvent is approximated by a pote ntial of mean force depending on the solvent accessible surface area. The m ethod has been successfully applied to N-acetyl-L-alanine-N-methylamide (al anine dipeptide), sampling experimentally observed conformations inaccessib le to MD alone under the chosen conditions. The method predicts correctly t he increased partial flexibility of the mutant Y35G compared to native bovi ne pancreatic trypsin inhibitor. Tn particular, the improvement over MD con sists of the detection of conformational flexibility that corresponds close ly to dow motions identified by nuclear magnetic resonance techniques. (C) 2000 Federation of European Biochemical Societies.