(479d) Uncovering the Role of Water in Biomolecular Interactions

The Protein Data Bank contains structures of over 75,000 proteins with atomic resolution, and is growing exponentially. Translating this wealth of static structural information into a molecular understanding of dynamic intracellular processes represents a grand challenge, with progress hinging on our ability to understand biomolecular interactions. Water plays a crucial role in mediating these interactions, in particular through non-specific hydrophobic effects. However, characterizing protein hydrophobicity (and consequently interactions) is challenging, as it depends not only on the chemistry of the underlying surface, but also on surface topography, chemical patterning, size/shape of ligand, etc. We have shown that such context-dependent hydrophobicity depends, not on the mean water density near the protein surface, but on the ease of displacing water from the interfacial region, or alternatively, on the cost of forming cavities near the surface. We have developed novel molecular simulation techniques to efficiently calculate cavity formation free energies. Collectively, our results provide a computational framework for mapping the hydrophobicity of proteins and other complex surfaces, with relevance to developing predictive strategies for biomolecular binding, recognition, and aggregation. Our results also shed light on the driving forces and barriers to hydrophobically driven binding and assembly in interfacial environments. Specifically, we show that water near hydrophobic surfaces is situated at the edge of a dewetting transition that can be triggered by small perturbations. This perspective provides unique insights into diverse phenomena ranging from the formation of amyloid fibrils catalyzed by interfaces, and the function of chaperonins, to the vapor-lock gating mechanism of ion channels.