LOCALLY ACCESSIBLE CONFORMATIONS OF PROTEINS - MULTIPLE MOLECULAR-DYNAMICS SIMULATIONS OF CRAMBIN

Multiple molecular dynamics (MD) simulations of crambin with different initial atomic velocities are used to sample conformations in the vic inity of the native structure. Individual trajectories of length up to 5 ns sample only a fraction of the conformational distribution genera ted by ten independent 120 ps trajectories at 300 K. The backbone atom conformational space distribution is analyzed using principal compone nts analysis (PCA). Four different major conformational regions are fo und. In general, a trajectory samples only one region and few transiti ons between the regions are observed. Consequently, the averages of st ructural and dynamic properties over the ten trajectories differ signi ficantly from those obtained from individual trajectories. The nature of the conformational sampling has important consequences for the util ization of MD simulations for a wide range of problems, such as compar isons with X-ray or NMR data. The overall average structure is signifi cantly closer to the X-ray structure than any of the individual trajec tory average structures. The high frequency (less than 10 ps) atomic f luctuations from the ten trajectories tend to be similar, but the lowe r frequency (100 ps) motions are different. To improve conformational sampling in molecular dynamics simulations of proteins, as in nucleic acids, multiple trajectories with different initial conditions should be used rather than a single long trajectory.