Folding of a SH3 Domain: Standard and "Hydrodynamic" Analyses

Discrete mol. dynamics has been used to study the folding of a SH3 domain with a Cα-​based Go-​model at a temp. within the native state stability region. A std. anal. of the folding process, based on consideration of the mean-​force (free energy) surfaces, contact maps and folding time distributions, is complemented by a "hydrodynamic" Chekmarev's description of folding flows using two and three collective variables. Two types of folding trajectories (fast and slow) follow essentially different routes in the final stage of folding. The hydrodynamic description makes possible the calcn. of folding flows corresponding to these routes. The results show that the probability flows do not correspond to the free energy surface and that vortex formation is involved in the slow trajectories. Comparison of the simulation results with the exptl. data suggests that the two-​state kinetics obsd. for Fyn and Src SH3 domain folding are assocd. with the slow trajectories, in which a partly formed N- and C-​terminal β sheet hinders the RT-​loop from attaching to the protein core; the fast trajectories are not obsd. because they are in the dead time (1 ms) of the expts.