Water, despite being a driving force in biochemical processes, has an elusively complex microscopic behavior. For instance, water can increase its local density near amphiphilic protein surfaces and also evaporate from hydrophobic surfaces and cavities, an effect known as ‘dewetting’. While an atomistic, explicit description of water can be too expensive in large biomolecular systems, most implicit solvent methods fail to capture dewetting effects and heterogeneous hydration by relying on pre-established (i.e. guessed) solvation interfaces In contrast with such methods, the Variational Implicit Solvent Method (VISM) is an implicit solvent method that includes water ‘plasticity’ in the picture by formulating the solvation free energy as a functional of all possible solvation interfaces. By minimizing this functional, VISM produces the solvation interface as an output of the calculations. Also, minimization of the VISM functional can lead to distinct solvation interfaces (depending on the initial guess), indicating the existence of multiple hydration states. Here, we describe how VISM is being tailored to deal with biological systems such as proteins, whose complex topology often produces heterogeneous hydration effects. Specifically, we show how VISM can correctly describe hydration in the molecular recognition of two distinctive protein-protein complexes – the hydrophilic barstar-barnase and the hydrophobic MDM2-p53 – in good agreement with atomistic, explicit solvent molecular dynamics simulations. The advances and results reported herein encourage us to combine VISM with molecular simulations to obtain a new biophysical method that is able to efficiently describe complex heterogeneous hydration in large biomolecular systems.

Tailoring the variational implicit solvent method (VISM) for new challenges: Heterogeneous hydration in biomolecular recognition

2019 Fall National Meeting

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