Biological and Medicinal Chemistry

Predicting and Experimentally Validating Hot-Spot Residues at Protein-Protein Interfaces

Abstract

Here we describe a comparative analysis of multiple CAS methods, which highlights effective approaches to improve the accuracy of predicting hot-spot residues. Alongside this, we introduce a new method, BUDE Alanine Scanning, which can be applied to single structures from crystallography, and to structural ensembles from NMR or molecular dynamics data. The comparative analyses facilitate accurate prediction of hot-spots that we validate experimentally with three diverse targets: NOXA-B/MCL-1 (an α helix-mediated PPI), SIMS/SUMO and GKAP/SHANK-PDZ (both β strand-mediated interactions). Finally, the approach is applied to the accurate prediction of hot-residues at a topographically novel Affimer/BCL-xL protein-protein interface.

Version notes

version 1.0

Content

Thumbnail image of Predicting and Experimentally Validating Hot Residues Manuscript 01-07-19.pdf
download asset Predicting and Experimentally Validating Hot Residues Manuscript 01-07-19.pdf 1 MB [opens in a new tab]

Supplementary material

Thumbnail image of Predicting and Experimentally Validating Hot Residues Manuscript SI 01-07-19.pdf
download asset Predicting and Experimentally Validating Hot Residues Manuscript SI 01-07-19.pdf 3 MB [opens in a new tab]
Predicting and Experimentally Validating Hot Residues Manuscript SI 01-07-19