CONFORMATIONAL TRANSITIONS USING MOLECULAR-DYNAMICS WITH MINIMUM BIASING

The molecular dynamics algorithm (MD), which simulates intramolecular motions on the subnanosecond timescale, has been modified to allow the investigation of slow conformational transitions that do not necessar ily occur spontaneously in MD simulations. The method is designated CO NTRA MD (CONformational TRAnsitions by Molecular Dynamics with minimum biasing). The method requires the prior definition of a single confor mational variable that is required to vary monotonically from an initi al conformation to a final target conformation. The simulation is brok en up into a series of short free MD segments, and we determine, after each segment of MD, whether or not the system has evolved toward the final conformation. Those segments that do not move the system in that direction are deleted. Those that do move it toward the final conform ation are patched together sequentially to generate a single represent ative trajectory along the transition pathway. The CONTRA MD method is demonstrated first by application to the simultaneous C2'-endo to C3' -endo repucker and anti to syn N-glycosidic torsion transitions in 2'- deoxyadenosine and then to the large-scale bending in phenylalanine tr ansfer RNA.