3.3 Uniqueness of Arg, Tyr and Leu makes them favourite residues
for interaction
Dividing the hotspots into a three different types has revealed the
subtle characteristic patterns of hotspots. Arg is the clear choice
among the strong types of hotspots and anchor residues in either of the
protein-protein and protein-peptide interfaces. Why Arg is the highly
preferred hotspot and anchor residue for interactions? The overwhelming
presence of Arg residue as hotspot at the interacting interface stems
from a multitude of facts [10]. The guanidinium group of Arg is one
of the weakliest hydrated cations due to charge delocalization. This
makes the Arg side chain easier to bury [46] as compared to other
hydrophobic residues [47]. The anchor residue calculations suggest
the predominant occurrence of Arg with ΔSASA (unbound – bound) area
ranging from 101-205 Å2, quantitatively indicating
that it has the ability to substantially bury its surface. Buried Arg
side chain has several advantages as compared to other residues. It is
charged, extensively hydrogen-bonded (can donate up to 5 hydrogen
bonds), having high pK, high flexibility to interact, and also possess
the ability to interact by stacking with other planar side chain groups
in proteins [46, 48, 49]. Thus among 5-charges residues, Arg was
selected in nature to mediate protein-protein and protein-peptide
interactions.
Similarly, examining the overall trend (Fig. 1 and Table 2), Tyr and Leu
are highly preferred ones among polar and hydrophobic residues. These
amino acids possess a striking balance of flexibility, rigidity and
steric bulk. The amino acids having sufficient steric bulk and
flexibility is required to generate a structurally plastic regions
enabling the binding interface to mold itself to optimize
complementarity. Additionally, the physicochemical properties of
tyrosine i.e. amphipathic and bulky side chain, which is capable of
forming nonpolar, hydrogen-bonding, cation-π and π-π stacking
interactions, making it one of the most effective polar residues for
mediating molecular recognition [50].