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

submitted on 02.07.2019, 22:24 and posted on 03.07.2019, 18:26 by Amaurys Ibarra, Gail J. Bartlett, Zsofia Hegedus, Som Dutt, Fruzsina Hobor, Katherine Horner, Kristina Hetherington, Kirstin Spence, Adam Nelson, Thomas Edwards, Derek N Woolfson, Richard Sessions, Andrew Wilson
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.


EPSRC - EP/N013573/1

EPSRC - EP/KO39292/1

EPSRC - EP/N025652/1

ERC - 340764

Wellcome Trust - 097827/Z/11/A

Wellcome Trust - WT094232MA

Wellcome Trust - 094232/Z/10/Z

Royal Society - WM140008


Email Address of Submitting Author


University of Leeds


United Kingdom

ORCID For Submitting Author


Declaration of Conflict of Interest

No Conflict of Interest

Version Notes

version 1.0