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Recent work has shown that the hydrophobic protein surfaces in aqueoussolution sit near a drying transition. The tendency for these surfaces to expelwater from their vicinity leads to self assembly of macromolecular complexes.In this article we show with a realistic model for a biologically pertinentsystem how this phenomenon appears at the molecular level. We focus on theassociation of the C-terminal domain (CA-C) of the human immunodeficiency virus(HIV) capsid protein. By combining all-atom simulations with specializedsampling techniques we measure the water density distribution during theapproach of two CA-C proteins as a function of separation and amino acidsequence in the interfacial region. The simulations demonstrate that CA-Cprotein-protein interactions sit at the edge of a dewetting transition and thatthis mesoscopic manifestation of the underlying liquid-vapor phase transitioncan be readily manipulated by biology or protein engineering to significantlyaffect association behavior. While the wild type protein remains wet untilcontact, we identify a set of in silico mutations, in which three hydrophilicamino acids are replaced with nonpolar residues, that leads to dewetting priorto association. The existence of dewetting depends on the size and relativelocations of substituted residues separated by nm length scales, indicatinglong range cooperativity and a sensitivity to surface topography. Theseobservations identify important details which are missing from descriptions ofprotein association based on buried hydrophobic surface area.

Simulations of HIV capsid protein dimerization reveal the effect of chemistry and topography on the mechanism of hydrophobic protein association