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The high temperature requirement A (HtrA) protease plays a crucial role in protein quality control and cell fate. The enzyme contains a catalytic protease domain and a regulatory PDZ domain; the latter determines the sub­strate specificity of the former by specifically binding to the C-terminal hyd­ro­phobic stretch of its partner proteins. Previously, a pentapeptide ligand H3C1 was identified as the potential binder of HtrA PDZ domain using phage display technique. Here, an orthogonal π–cation–π stacking system at the crystal domain–peptide complex interface was analysed by integrating theoretical calcul­at­ions and experimental assays. It was demonstrated that there is a strong (positive) synergistic effect between the two wings of the stacking system; breaking of cation–π interaction in one wing can largely impair the interaction strength of another wing. The π-electron contributes primarily to the syner­gistic effect, although geometric property is also (marginally) responsible for it. Next, the systematic combinations between the four aromatic amino acids (Phe, Tyr, Trp and His) plus one non-aromatic amino acid (Ala) at the two wings of π–cation–π stacking were investigated. It was found that two aromatic substitutions (Phe-4Tyr and Phe-4Trp) at a wing can considerably and moder­ately improve pep­tide affinity by 3.2- and 1.5-fold, respectively, whereas the non-aromatic mut­ations at each wing and at both of them can significantly reduce the affinity with K d increase from 1.8 (wild type) to 34 μM and 160 μM (single-point mutations), as well as 210 μM (double-point mutation), suggest­ing that just breaking of one wing can substantially undermine the synergism of orthogonal π–cation–π stacking.

Molecular design of orthogonal stacking system at the complex interface of HtrA PDZ domain with its peptide ligands