Pressure Effects on Protein Hydration Water Thermodynamics

Abstract

In this molecular dynamics simulation study, we analyze the impact of increasing hydrostatic pressure on the solvation of protein surfaces. Apart from the increasing volume work required for the formation of the protein solute cavity at high hydrostatic pressures, no significant additional trend is observed for solvation free energy contributions due to the protein−water interactions analyzed here. The latter is the result of approximately canceling pressure-induced changes of enthalpic and entropic solvation free energy contributions, which can be traced back to changes in the hydration of hydrophilic and hydrophobic groups of the protein. The 3D-2PT analysis used here allows for the visualization of local solvation free energy contributions in three dimensions with high spatial resolution. Local solvation free energy contributions per water molecule at hydrophobic surfaces are small but mainly favorable for transfer processes from the gas phase. This does not change considerably with increasing pressure, while the number of hydrating water molecules increases due to increased packing of the hydration shell. The number of hydrating water molecules also increases for hydrophilic protein surfaces, but solvation contributions per water molecule become less favorable with pressure in this case. As a consequence, contributions to the total solvation free energy from interactions between water molecules and hydrophobic surfaces become increasingly relevant at high hydrostatic pressures. Our results provide novel insights into solvent-mediated contributions to the thermodynamic driving force of pressure denaturation of proteins.

Solvent‐mediated forces in protein dielectrophoresis

“…Several recent methods allow for detailed insights into the solvation of biomolecules from equilibrium MD simulations in explicit solvents [18, 19, 33–36]. Local contributions to the total solvation free energy, enthalpy and entropy in the biomolecular environment can be spatially resolved for additional insight.…”

“…These microstates were then used as starting points for 100 ps simulations in the microcanonical NVE (constant number of particles, volume and energy) ensemble, which were used to carry out the 3D‐2PT (where 2PT is two‐phase thermodynamics) analysis of the solvation free energy (see next section). For these simulations, coordinates and velocities were saved every 8 fs to allow for the sampling of all relevant frequencies in the vibrational density of states, which are used in the 3D‐2PT framework to estimate the local entropy of solvent molecules [17, 19, 30, 31]. All simulations in the microcanonical ensemble used an integration time step of 1 fs, while simulations involving thermostats used a 2 fs integration time step.…”

“…For the a posteriori analysis of intermolecular interactions, a real‐space cutoff of 12 Å was applied to the minimum distance between any two atoms of the interacting water molecules or amino acid residues. Averages over all NVE trajectories were used to obtain enthalpic contributions to the solvation enthalpy as described previously [17, 19], while voxels with a minimum distance of 12 Å to the nearest protein atom were defined as bulk water. To obtain information on local contributions to the solvation entropy, time correlation functions of the center of mass velocity as well as for the angular velocity around each moment of inertia were computed for each water molecule.…”

“…Gradients of the solvation free energy in the presence of inhomogeneous electric fields create a solvent‐mediated DEP force, which has not been included in previous theoretical considerations. A spatially resolved analysis of local solvation free energy contributions [17–19] and their field‐induced changes allows us to further obtain direct microscopic insights into the molecular origins of solvent‐mediated DEP forces. While the solvent‐mediated DEP forces are found to play a minor role for the studied systems, we predict scenarios in which solvent‐mediated contributions may become a dominant factor for protein DEP.…”

Controlling Protein Nanocage Assembly with Hydrostatic Pressure

“…30,31 In addition, the solvation of hydrophobic surfaces becomes increasingly favored. 32 similar manner to chaotropes such as guanidine or urea. This leads to conformational drift that further disrupts interfacial interactions and results in hysteresis in reassociation on pressure release.…”