Protein Surface Mimetics: Understanding How Ruthenium Tris(Bipyridines) Interact with Proteins

Sarah H. Hewitt; Maria H. Filby; Ed Hayes; Lars T. Kuhn; Arnout P. Kalverda; Michael E. Webb; Andrew J. Wilson

doi:10.1002/cbic.201600552

Protein Surface Mimetics: Understanding How Ruthenium Tris(Bipyridines) Interact with Proteins

Sarah H. Hewitt, Maria H. Filby, Ed Hayes, Lars T. Kuhn, Arnout P. Kalverda, Michael E. Webb, Andrew J. Wilson^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

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 ¹H,¹⁵N 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.

Original language	English
Pages (from-to)	223-231
Number of pages	9
Journal	ChemBioChem
Volume	18
Issue number	2
DOIs	https://doi.org/10.1002/cbic.201600552
Publication status	Published - 17 Jan 2017

Bibliographical note

Funding Information:
The authors wish to Prof. Mike Knapp (UMass, Amherst) for the gift of the CCP plasmid and Taylor Page (Prof. Brian Hoffman's group at Northwestern University) for sharing the modified purification procedure. This work was supported by the Engineering and Physical Sciences Research Council [EP/L504993/1, EP/F039069/1, EP/F038712/1 and EP/KO39292/1] and the Wellcome Trust [108466/Z/15/Z].

Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

molecular recognition
protein surface recognition
protein–protein interactions
receptors
supramolecular chemistry

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Organic Chemistry

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10.1002/cbic.201600552

Cite this

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title = "Protein Surface Mimetics: Understanding How Ruthenium Tris(Bipyridines) Interact with Proteins",

abstract = "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 1H,15N 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.",

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note = "Funding Information: The authors wish to Prof. Mike Knapp (UMass, Amherst) for the gift of the CCP plasmid and Taylor Page (Prof. Brian Hoffman's group at Northwestern University) for sharing the modified purification procedure. This work was supported by the Engineering and Physical Sciences Research Council [EP/L504993/1, EP/F039069/1, EP/F038712/1 and EP/KO39292/1] and the Wellcome Trust [108466/Z/15/Z]. Publisher Copyright: {\textcopyright} 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

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AU - Kalverda, Arnout P.

AU - Webb, Michael E.

AU - Wilson, Andrew J.

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N2 - 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 1H,15N 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.

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Protein Surface Mimetics: Understanding How Ruthenium Tris(Bipyridines) Interact with Proteins

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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