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Protein Surface Mimetics: Understanding How Ruthenium Tris(Bipyridines) Interact with Proteins
Author(s) -
Hewitt Sarah H.,
Filby Maria H.,
Hayes Ed,
Kuhn Lars T.,
Kalverda Arnout P.,
Webb Michael E.,
Wilson Andrew J.
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600552
Subject(s) - chemistry , supramolecular chemistry , non covalent interactions , molecular recognition , ruthenium , tris , protein–protein interaction , binding site , scaffold protein , combinatorial chemistry , stereochemistry , biophysics , biochemistry , hydrogen bond , molecule , signal transduction , organic chemistry , biology , catalysis
Protein surface mimetics achieve high‐affinity binding by exploiting a scaffold to project binding groups over a large area of solvent‐exposed protein surface to make multiple cooperative noncovalent interactions. Such recognition is a prerequisite for competitive/orthosteric inhibition of protein–protein interactions (PPIs). This paper describes biophysical and structural studies on ruthenium(II) tris(bipyridine) surface mimetics that recognize cytochrome (cyt) c and inhibit the cyt c /cyt c peroxidase (CCP) PPI. Binding is electrostatically driven, with enhanced affinity achieved through enthalpic contributions thought to arise from the ability of the surface mimetics to make a greater number of noncovalent interactions than CCP with surface‐exposed basic residues on cyt c . High‐field natural abundance 1 H, 15 N HSQC NMR experiments are consistent with surface mimetics binding to cyt c in similar manner to CCP. This provides a framework for understanding recognition of proteins by supramolecular receptors and informing the design of ligands superior to the protein partners upon which they are inspired.