Exploring free energy landscapes of large conformational changes: molecular dynamics with excited normal modes.

Proteins are found in solution as ensembles of conformations in dynamic equilibrium. Exploration of functional motions occurring on micro- to millisecond time scales by molecular dynamics (MD) simulations still remains computationally challenging. Alternatively, normal mode (NM) analysis is a well-suited method to characterize intrinsic slow collective motions, often associated with protein function, but the absence of anharmonic effects preclude a proper characterization of conformational distributions in a multidimensional NM space. Using both methods jointly appears to be an attractive approach that allows an extended sampling of the conformational space. In line with this view, the MDeNM (molecular dynamics with excited normal modes) method presented here consists of multiple-replica short MD simulations in which motions described by a given subset of low-frequency NMs are kinetically excited. This is achieved by adding additional atomic velocities along several randomly determined linear combinations...