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].