Predicting slow structural transitions in macromolecular systems: Conformational flooding

Abstract

We present a method to predict complex structural (conformational) transitions in irregular or disordered macromolecular systems, such as proteins or glasses, at the atomic level. Our method aims at rare events, which currently cannot be predicted with traditional molecular dynamics (MD) simulations, since these currently are limited to time scales shorter than a few nanoseconds. Given an initial conformation of the system, our method identifies one or more product states, which may be separated from the initial state by free energy barriers that are large on the scale of thermal energy. It also provides an approximate reaction path, which can be used to determine barrier heights or reaction rates with the usual techniques. The method employs an artificial potential that destabilizes the initial conformation and, thereby, lowers free energy barriers of structural transitions. As a result, transitions are accelerated and may be observed in MD simulations. An analytical estimate for the acceleration factor is given. The method is applied to two test systems, an argon microcluster and a simplified protein model. By these studies we demonstrated that our method is capable of shortening mean transition times from 0.5 \ensuremath{\mu}s (argon cluster) and 1.4 ns (protein model) to a few picoseconds. These results suggest that our method is particularly well suited to study biochemically relevant conformational motions in proteins at a microsecond time scale.