Characterization of Hydrophilic α-Helical Hot Spots on the Protein-Protein Interaction Interfaces for the Design of α-Helix Mimetics

The cooperativity index, K-c, was developed to examine the binding synergy between hot spots of the ligand-protein. For the first time, the convergence of the side-chain spatial arrangements of hydrophilic alpha-helical hot spots Thr, Tyr, Asp, Asn, Ser, Cys, and His in protein-protein interaction (PPI) complex structures was disclosed and quantified by developing novel clustering models. In-depth analyses revealed the driving force for the protein-protein binding conformation convergence of hydrophilic alpha-helical hot spots. This observation allows deriving pharmacophore models to design new mimetics for hydrophilic alpha-helical hot spots. A computational protocol was developed to search amino acid analogues and small-molecule mimetics for each hydrophilic alpha-helical hot spot. As a pilot study, diverse building blocks of commercially available nonstandard L-type alpha-amino acids and the phenyl ring-containing small-molecule fragments were obtained, which serve as a fragment collection to mimic hydrophilic alpha-helical hot spots for the improvement of binding affinity, selectivity, physicochemical properties, and synthesis accessibility of alpha-helix mimetics.

Automated summary

The cooperativity index, Kc, was developed to examine the binding synergy between hot spots of the ligand-protein. The spatial arrangements of hydrophilic alpha-helical hot spots in protein-protein interaction (PPI) complex structures were disclosed and quantified using novel clustering models. The driving force for the convergence of these hot spots was analyzed, allowing the development of pharmacophore models for designing new mimetics.