Investigation of Low Temperature Protein Folding at Ambient and High Pressure Using Molecular Simulation

Recent all-atom molecular simulation work by our group has demonstrated that water’s anomalous properties at low temperatures (>50 K below freezing) can drive the unexpected re-folding of a small peptide, Trp-cage, at ambient pressure (J. Chem. Phys. 151, 185101 (2019); https://doi.org/10.1063/1.5128211). Here, we extend this work by investigating the folding behavior of a larger peptide, the Villin headpiece, at ambient and high pressure (the latter at conditions proximal to where the solvent, water, is hypothesized to possess a liquid-liquid critical point). As in our recent work, we employ a combination of Parallel Tempering and Well-Tempered Metadynamics to overcome kinetic sampling barriers at low temperatures and show that folding thermodynamics from initially folded and initially unfolded states converge. In this way, we are able to study the effects of critical fluctuations on protein folding thermodynamics.