With the development of ANTON, a special-purpose supercomputer, it has recently become possible to perform all-atom Molecular Dynamics (MD) simulations of the reversible folding of a number of small globular proteins. This progress has allowed to confirm that the existing force fields are indeed sufficiently accurate to predict the existence of protein native states, and to yield predictions for the folding reaction kinetics which are in good agreement with experiment. On the other hand, many protein folding reactions are so complex and so slow to lie well beyond the reach of any present or foreseen MD simulations, even on dedicated machines or using world-wide distributed computing.
In order to investigate the dynamics of these reactions in atomistic detail, one needs to resort on alternative theoretical methods and algorithms. In particular, the Dominant Reaction Pathways (DRP) is a path-integral based variational approach which yields the reaction pathways with the highest statistical weights.
In order to briefly introduce the DRP algorithm in its present implementation I will first discuss our benchmarkbased on the folding of the FIP3WW domain, a small protein which had been extensively studied on ANTONusing standard MD. I will then discuss how the same method has been used to study, within the same atomistic model, the much more complex folding of an 83-residue knotted protein.
In the last part of this talk, I will present our recent results on the native-to-latent transition of a set of evolutionary related serpin proteins, a 370 amino acids polypeptide which is at the origin of misfolding pathologies called serpinopaties. Although the reaction times for some of these protein transition can extend from a few minutes up to even several days, many atomistic DRP trajectories have been produced, which explain essentially all the available experimental information. In particular, we discuss the differences in the kinetics of the serpin mutants. These simulations reveal the existence of a pre-latent state which has been speculated as an intermediate along the route to the misfolded state.
Some selected references: "Dominant Folding Pathways of a WW Domain", S. a Beccara, T. Skrbic, R. Covino and PF, Proc. Natl.Acad. Sci. USA 109, 2330 (2012). "Folding of a Knotted Protein From a Realistic All Atom Force Field", T. Skrbic, S. a Beccara, R. Covino, C.Micheletti and PF, PLoS Com. Biol. 9, e1003002 (2013). "The Role of Non-Native Interactions in the Folding of Knotted Proteins", T. Skrbic C. Micheletti and PF,PLoS Comp. Biol. 8 e1002504 (2012).