Computer simulations of protein folding by targeted molecular dynamics

We have performed 128 folding and 45 unfolding molecular dynamics runs of c hymotrypsin inhibitor 2 (C12) with an implicit solvation model for a total simulation time of 0.4 microseconds. Folding requires that the three-dimens ional structure of the native state is known. It was simulated at 300 K by supplementing the force held with a harmonic restraint which acts on the ro ot-mean-square deviation and allows to decrease the distance to the target conformation. High temperature and/or the harmonic restraint were used to i nduce unfolding. Of the 62 folding simulations started from random conforma tions, 31 reached the native structure, while the success rate was 83% for the 66 trajectories which began from conformations unfolded by high-tempera ture dynamics. A funnel-like energy landscape is observed for unfolding at 475 K while the unfolding runs at 300 K and 375 It as well as most of the f olding trajectories have an almost flat energy landscape for conformations with less than about 50% of native contacts formed. The sequence of events, i.e., secondary and tertiary structure formation, is similar in all foldin g and unfolding simulations, despite the diversity of the pathways. Previou s unfolding simulations of CI2 performed with different force fields showed a similar sequence of events. These results suggest that the topology of t he native state plays an important role in the folding process. (C) 2000 Wi ley-Liss, Inc.