Role of solvation in pressure-induced helix stabilization

Abstract

In contrast to the well-known destabilization of globular proteins by high pressure, recent work has shown that pressure stabilizes the formation of isolated α-helices. However, all simulations to date have obtained a qualitatively opposite result within the experimental pressure range. We show that using a protein force field (Amber03w) parametrized in conjunction with an accurate water model (TIP4P/2005) recovers the correct pressure-dependence and an overall stability diagram for helix formation similar to that from experiment; on the other hand, we confirm that using TIP3P water results in a very weak pressure destabilization of helices. By carefully analyzing the contributing factors, we show that this is not merely a consequence of different peptide conformations sampled using TIP3P. Rather, there is a critical role for the solvent itself in determining the dependence of total system volume (peptide and solvent) on helix content. Helical peptide structures exclude a smaller volume to water, relative to non-helical structures with both the water models, but the total system volume for helical conformations is higher than non-helical conformations with TIP3P water at low to intermediate pressures, in contrast to TIP4P/2005 water. Our results further emphasize the importance of using an accurate water model to study protein folding under conditions away from standard temperature and pressure.

Water Mediated Interactions and the Protein Folding Phase Diagram in the Temperature–Pressure Plane

“…The fraction of native structure for each residue is shown visually in Figure 4a in ∆G f −u is small and almost certainly within the statistical error in the study. [44][45][46][47][48] It is difficult to distinguish between the native and denatured ensembles using the radius 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37...…”

Pressure‐induced structural transition of mature HIV‐1 protease from a combined NMR/MD simulation approach

“…S5 and Table S3). The TIP4P/2005 water model was used for its ability to capture pressure‐dependent equilibria, in conjunction with the Amber ff99SBws protein force field optimized for this water model . The simulation pressure was set to be the same as in experiment.…”

Thermodynamic stability of hnRNP A1 low complexity domain revealed by high‐pressure NMR

“…23 Separately, it has been reported that folding of small helical motifs can be promoted under high-pressure conditions due to preferential hydration of helical structure. [25][26][27] These evidences suggest that unfolded protein chains may not remain entirely featureless at high-pressure.…”