Folding Mechanism of Proteins IM7 and IM9, from Computer Simulations in a Realistic Atomistic Force Field

Abstract

IM7 and IM9 are small evolutionarily related proteins which fold according to different kinetics, in spite of their remarkable structural homology. While the former chain clearly folds according to three-state kinetics, the evidence for an on-pathway intermediate in the folding of IM9 is much more elusive. This observation has triggered considerable theoretical and experimental effort, aiming to characterize the folding pathways of these chains and clarify the physical origin of the observed differences. In this work, we use the Dominant Reaction Pathway (DRP) method to efficiently generate many folding trajectories for these proteins, from a realistic atomistic force field. Overall, our results are found to be in good agreement with with experimental φ-values and with the result of φ-value-restrained Molecular Dynamics (MD) simulation, and suggest that the differences in the folding pathways and kinetics is largely influenced by the chains’ native topology. On the other hand,by performing MD simulations starting from the calculated on-pathway intermediates we argue that the difference in the life-times of the two on-pathway intermediates is due to non-native electrostatic interactions between specific residues and the solvent.