Force field molecular dynamics at high hydrostatic pressures: Water, osmolytes, and peptides

Understanding water and aqueous solutions of biomolecules at high hydrostatic pressure is important not only for the research of deep sea life, but also for gaining insight into properties relevant to ambient conditions. Some small organic molecules, called osmolytes, can stabilize or destabilize the native conformation of proteins in cells against external stresses like temperature and pressure. We use force field molecular dynamics simulations to study the influence of selected osmolytes on water and proteins solutions with respect to their response to high hydrostatic pressure. This is achieved using different approaches, which are aimed to lay the foundations for understanding and being able to simulate osmolytes at high pressures and then applying these fundamental results to more realistic systems: 1. We present a detailed analysis of the structure of pure water close to a hydrophobic alkane monolayer, which serves as a model system for studying hydrophobic solvation, up to 10 kilobars of pressure. The structural properties of interest include the frequency and geometry of rings in the hydrogen bond network, from which we deduce that the instantaneous structure of water at this hydrophobic interface increases its likeness to hexagonal ice with increasing pressure. 2. We show that it is necessary to modify the force field parameters of the protecting osmolyte trimethylamine-N-oxide (TMAO) in order to correctly reproduce its solvation structure at high pressures, and we present a systematic procedure for scaling the partial charges. For the most relevant protein denaturant, urea, we develop a new force field for aqueous solutions which significantly improves upon existing literature models at normal pressure and in the high pressure range. 3. We apply the transfer model to periodic glycine and alanine homopeptides in different secondary structures to show that helical conformations of these peptides are stabilized by TMAO even at 5 kilobars relative to an extended structure. 4. We simulate folding of the Trp-cage miniprotein in water and in TMAO solution at normal and high pressures. We find some evidence that the protecting effect of TMAO on the tertiary structure of Trp-cage is weaker but still present at 10 kbar.