Accelerating protein unfolding simulations: Effect of ionic liquids on villin headpiece unfolding time

Abstract

We demonstrate an approach to accelerate protein unfolding simulation using the metadynamics (MetaD) method, and the new rate calculation method “infrequent metadynamics”. The accelerated simulation time can be 200 ~ 700 times faster than normal molecular dynamics (MD) simulations. Using protein villin headpiece (HP35) as an example, we are the first to this approach to systematically investigate the effect of ionic liquids (ILs) on protein unfolding time. We reveal HP35 unfolding time in four different 20 % (w/w) ILs / water mixtures. Comparing to experimental results of ribonuclease A (RNase A), we find the anion’s ability to decrease protein unfolding time shares the same order as our simulation results. A detailed examination of protein and solvent behavior at molecular-level supports the current view in the literature about protein stability in ILs; namely that the ion-protein interaction play a more significant role than the ion-induced change in the bulk water structure. This study provides the understanding of effects of ILs on protein stability and makes the achievement of calculating protein unfolding times in a greatly accelerated timescale.