Identifying hydrophobic protein patches to inform protein interaction interfaces

Significance Hydrophobicity drives diverse aqueous assemblies, including the interactions between proteins. Conventional wisdom stipulates that the hydrophobicity of a surface must be inversely related to its polarity. By using specialized molecular simulations to characterize protein hydrophobicity, here, we challenge this notion and demonstrate that polar/charged atoms comprise a substantial fraction of hydrophobic protein patches. Moreover, hydrophobic and hydrophilic protein patches have surprisingly similar chemical compositions. We further find that the most hydrophobic protein patches also tend to mediate protein interactions. Our work thus establishes a computational framework for characterizing the hydrophobicity of complex solutes, such as proteins, and for uncovering their interaction interfaces.