MD Modeling of Oxidative Folding in Peptides and Proteins

Abstract

We are now at the dawn of the new era in protein modeling when it becomes possible to fold proteins in silico “from the first principles”, i.e. using unbiased MD simulations. We have developed an empirical protocol to include the process of disulfide bonding into conventional (unrestrained) MD models of protein folding. The protocol has been tested on 15-amino-acid peptide guanylin, containing four cysteine residues. The fifty guanylin trajectories recorded with GPU-enabled Amber 14 program under ff14SB force field produced thirty eight disulfide-bonded folds, with the isomer distribution that is broadly similar to the one observed experimentally. The PBSA/GBSA energy calculations performed on these MD models suggest that the isomer distribution is under kinetic rather than thermodynamic control. We have also used the new protocol to simulate disulfide bonding in the terminal guanylin segment within the 94-amino-acid prohormone proguanylin. It is envisaged that in future an efficient reactive force field can be constructed along these lines to model protein oxidative folding.