Common Structural Features of Hydrophobic α-Helical Hot Spots: Insights for the Design of Novel α-Helix Mimetics

The binding conformations of alpha-helical hydrophobic hot spots are convergent into two spatial areas in protein-protein complex structures. The physical basis for convergence was disclosed, which allows the development of pharmacophore models for i/i + 4/i + 7 or i/i + 3/i + 4 alpha-helical hot spots. Further investigation revealed that this convergence of binding conformations is common among all hydrophobic hot spots regardless of their alpha-helical positions. This observation led to a streamlined generation of pharmacophore models for hydrophobic hot spots at any positions along the alpha-helix. These successfully evaluated models be useful for novel alpha-helical hot mimetics.

Automated summary

The study reveals a convergence of binding conformations of alpha-helical hydrophobic hot spots in protein-protein complex structures, regardless of the position along the helix. This observation streamlines the development of pharmacophore models and may be useful for the design of novel alpha-helical hot spot mimetics.