  Recent work has shown that the hydrophobic protein surfaces in aqueous
solution sit near a drying transition. The tendency for these surfaces to expel
water from their vicinity leads to self assembly of macromolecular complexes.
In this article we show with a realistic model for a biologically pertinent
system how this phenomenon appears at the molecular level. We focus on the
association of the C-terminal domain (CA-C) of the human immunodeficiency virus
(HIV) capsid protein. By combining all-atom simulations with specialized
sampling techniques we measure the water density distribution during the
approach of two CA-C proteins as a function of separation and amino acid
sequence in the interfacial region. The simulations demonstrate that CA-C
protein-protein interactions sit at the edge of a dewetting transition and that
this mesoscopic manifestation of the underlying liquid-vapor phase transition
can be readily manipulated by biology or protein engineering to significantly
affect association behavior. While the wild type protein remains wet until
contact, we identify a set of in silico mutations, in which three hydrophilic
amino acids are replaced with nonpolar residues, that leads to dewetting prior
to association. The existence of dewetting depends on the size and relative
locations of substituted residues separated by nm length scales, indicating
long range cooperativity and a sensitivity to surface topography. These
observations identify important details which are missing from descriptions of
protein association based on buried hydrophobic surface area.
