Correlations between secondary structure- and protein–protein interface-mimicry: the interface mimicry hypothesis

Abstract

Preferred conformations of several peptidomimetics (specifically, minimalist mimics) were elucidated and compared with protein-protein interfaces on a huge scale, leading to a hypothesis regarding how these compounds mimic protein interface segments.

Piptides: New, Easily Accessible Chemotypes For Interactions With Biomolecules

“…Exploring Key Orientations on Secondary structures (EKOS) [24] was used to evaluate biases of preferred conformations of 10 aaa.I nE KOS, conformations of the mimic are simulated, preferred ones (within 3kcal mol À1 of the lowest energy conformation identified) are systematically overlaid on ideal secondary structures according to their three Ca-Cb vectors,a nd the fit of the superimpositions are evaluated in terms of the root mean square deviations (RMSDs) of the six Ca and Cb coordinates involved. We have shown, [24][25] superior secondary structure mimics overlay with RMSD values < 0.5 . 10 aaa is an excellent mimic of strand-turn-strand (Supporting Information, Figure S3), and parallel and antiparallel b-sheets.ARamachandran plot (Supporting Information, Figure S4) shows preferred conformers of 10 aaa are concentrated in anarrow range of f,ybond angles,indicative of conformational rigidity.…”

Query-guided protein–protein interaction inhibitor discovery

“…Whilst proteomimetics have been used to inhibit a range of intracellular α-helix-mediated PPIs, there remains a need to broaden the methodology to other targets and use the conceptual framework to identify small molecules that can be developed further. 63–66 This study also emphasizes that identification of non-α-helix mediated PPI inhibitors e.g. β-strand-mediated PPIs is more difficult, although the identification of inhibitors for a strand-mediated interaction with a PDZ domain, albeit with a significantly lower hit-rate represents the first steps towards such a goal.…”

Unconventional Secondary Structure Mimics: Ladder‐Rungs

“…beginning with non‐peptidic structures that present amino acid side‐chains (minimalist mimics), and exploration of where they fit on PPI interfaces. From the onset it was clear this approach provides insights into structures that resemble interface segments that have no recognizable secondary structures . However, we did not anticipate finding minimalist mimics that consistently overlay on interface secondary structures in an unpredictable way.…”