Three types of hotspots- weak, moderate and strong in protein-protein
and protein-peptide interactions
Abstract
Protein-protein and protein-peptide interactions (PPIs and PPepI) belong
to a similar category of interactions yet seemingly subtle differences
exist among them. To characterize differences between protein-protein
(PPI) and protein-peptide interactions (PPepI), we have focussed on two
important class of residues- hotspot and anchor residues. Using implicit
solvation-based free-energy calculations, a very large-scale alanine
scanning has been performed on benchmarking dataset, consisting of over
5500 interface residues. The differences in the two categories are more
pronounced, if the hotspot data is divided into three distinct types,
namely - weak hotspots (having binding free energy loss upon Ala
mutation, ΔΔG, 2-10 kcal/mol), moderate hotspots (ΔΔG, 10-20 kcal/mol)
and strong hotspots (ΔΔG ≥ 20 kcal/mol). The analysis suggests that for
PPI, weak hotspots are predominantly populated by polar and hydrophobic
residues. The distribution shifts towards charged and polar residues for
moderate hotspot and charged residues (principally Arg) are
overwhelmingly present in the strong hotspot. In contrast, in the PPepI
dataset, the distribution shifts from predominantly hydrophobic and
polar (in the weak type) to almost similar preference for polar,
hydrophobic and charged residues (in moderate type) and finally the
charged residue (Arg) and Trp are mostly occupied in the strong type. In
anchor residue class of both categories, the preferred residues are Arg,
Tyr and Leu, possesing bulky side chaing and which also strike a
delicate balance between side chain flexibility and rigidity. The
present knowledge should aid in effective design of biologics, when
augmentation or disruption of PPI are substituted with the peptide-based
mimics.