posted on 2023-11-24, 00:37authored byImee Sinha, Shekhar Garde, Steven M. Cramer
Protein surface hydrophobicity plays
a central role in various
biological processes such as protein folding and aggregation, as well
as in the design and manufacturing of biotherapeutics. While the hydrophobicity
of protein surface patches has been linked to their constituent residue
hydropathies, recent research has shown that protein surface hydrophobicity
is more complex and characterized by the response of water to these
surfaces. In this work, we employ water density perturbations to map
the surface hydrophobicity of a set of model proteins using sparse
indirect umbrella sampling simulations (SSI). This technique is used
to identify hydrophobic surface patches for the set of model proteins,
and the results are compared to those obtained from the widely adopted
spatial aggregation propensity (SAP) technique. While SAP-based calculations
show agreement with SSI in some cases, there are several examples
of disagreement. We identify four general classes of difference in
behavior and study factors that contribute to these differences. We
find that the SAP method can sometimes mask the effect of weakly nonpolar
or isolated nonpolar residues that can lead to strong hydrophobic
patches on the protein surface. In addition, hydrophobic patches identified
by SAP can exhibit shifts in both position and strength on the SSI
map. Our results demonstrate that the combination of topography and
chemical context controls the hydrophobicity of a given patch above
and beyond the intrinsic polarity of the residues present on the patch
surface. The availability of more accurate protein hydrophobicity
maps in concert with new classes of hydrophobic molecular descriptors
may create significant opportunities for in silico prediction of protein
behavior for a range of applications, such as protein design, biomanufacturability,
and downstream bioprocessing.