Health Innovation NOW Series: Conversation with Matthias Heyden from Arizona State University

Solvent-Mediated Driving Forces in (Bio)Molecular Systems:  Understanding direct intermolecular interactions in atomistic simulations on a qualitative or even semi-quantitative level is relatively straightforward with simplified empirical models that include just enough detail. For example, we can understand the consequences of Pauli repulsion and dispersion interactions between atoms or molecules using the Lennard-Jones potential. Likewise, we can understand electrostatic interactions and hydrogen bond formation between molecules using fitted partial charges that are assigned to individual atoms. All of the above are essential ingredients of molecular mechanics force fields used in atomistic molecular dynamics and Monte Carlo simulations.

However, even in such simplified representations of reality, one quickly realizes that in condensed systems, such as liquids and solutions, additional forces are at play, which are less trivial to describe. The latter are solvent-mediated interactions that result from the preferential solvation or desolvation of molecular interfaces and associated free energy changes. These interactions cannot be understood in terms of individual microstates (i.e. sets of coordinates), but require a thermodynamic ensemble for the solvent molecules. A popular example are hydrophobic interactions, which have been associated with protein folding and stability and many other self-assembly processes. However, also so-called hydrophilic solvent-mediated interactions are frequently observed in the form of water-mediated hydrogen bonds. Quantifying such indirect intermolecular interactions is non-trivial, but fundamentally important for our understanding of thermodynamic driving forces in chemistry and biochemistry.

We develop specialized tools that allow us to analyze solvation-induced free energy changes from atomistic molecular dynamics simulations with spatial resolution. Our methods allow us to compare the solvation of simple organic molecules with distinct substitution patterns, to quantify solvent-mediated interactions involved in protein conformational changes and complex formation, and to study the role of solvation for conformational ensembles of intrinsically disordered proteins.