(250g) Using Rare Water Fluctuations to Uncover the Principles Governing Protein Interactions and Mechanisms of Biological Assembly

Surfaces of proteins are both chemically as well as topographically heterogeneous, thereby making it challenging to identify general principles governing their interactions. Understanding of protein interactions is further complicated by the fact that they occur not in vacuum but in an aqueous medium. By studying how proteins affect hydration shell water, one can shed light on some of the underlying principles. Specifically, we quantify the ease with which water can be displaced from sub-volumes in hydration shells of proteins. Fluctuations required to completely empty water from a sub-volume can be quite rare. However, when the probability of emptying out water from a sub-volume next to a protein is greater than that in a similar volume in the bulk, it indicates a driving force to bind an ideal, purely repulsive hydrophobic solute to the protein. We show that monitoring of these rare fluctuations is indeed important to understanding protein interactions. These fluctuations become especially important (and less rare) in sub-volumes confined between two protein surfaces. The presence of a second hydrophobic surface can further destabilize water, leading to a spontaneous drying of the confined region and concomitant binding of the two proteins.