Role of solvation in pressure-induced helix stabilization

TL;DR

This study demonstrates that the choice of water model critically influences pressure-induced helix stabilization in proteins, with accurate models like TIP4P/2005 aligning simulations with experimental results.

Contribution

It shows that using an accurate water model (TIP4P/2005) with a suitable force field correctly reproduces pressure effects on helix stability, unlike simpler models like TIP3P.

Findings

TIP4P/2005 reproduces experimental pressure dependence of helix stability.

TIP3P water results in weak pressure destabilization of helices.

Solvent volume effects are crucial in helix stabilization under pressure.

Abstract

In contrast to the well-known destabilization of globular proteins by high pressure, re- cent work has shown that pressure stabilizes the formation of isolated {\alpha}-helices. However all simulations to date have obtained a qualitatively opposite result within the experimen- tal 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 experi- ment; 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.