Calculation of local water densities in biological systems: a comparison of molecular dynamics simulations and the 3D-RISM-KH molecular theory of solvation.

Water plays a unique role in all living organisms. Not only is it nature's ubiquitous solvent, but it also actively takes part in many cellular processes. In particular, the structure and properties of interfacial water near biomolecules such as proteins are often related to the function of the respective molecule. It can therefore be highly instructive to study the local water density around solutes in cellular systems, particularly when solvent-mediated forces such as the hydrophobic effect are relevant. Computational methods such as molecular dynamics (MD) simulations seem well suited to study these systems at the atomic level. However, due to sampling requirements, it is not clear that MD simulations are, indeed, the method of choice to obtain converged densities at a given level of precision. We here compare the calculation of local water densities with two different methods: MD simulations and the three-dimensional reference interaction site model with the Kovalenko-Hirata closure (3D-RISM-KH). In particular, we investigate the convergence of the local water density to assess the required simulation times for different levels of resolution. Moreover, we provide a quantitative comparison of the densities calculated with MD and with 3D-RISM-KH and investigate the effect of the choice of the water model for both methods. Our results show that 3D-RISM-KH yields density distributions that are very similar to those from MD up to a 0.5 Å resolution, but for significantly reduced computational cost. The combined use of MD and 3D-RISM-KH emerges as an auspicious perspective for efficient solvent sampling in dynamical systems.