NMR Spectroscopy of supramolecular chemistry on protein surfaces.

Peter Bayer,Christine Beuck,Anja Matena

doi:10.3762/bjoc.16.203

Abstract

As one of the few analytical methods that offer atomic resolution, NMR spectroscopy is a valuable tool to study the interaction of proteins with their interaction partners, both biomolecules and synthetic ligands. In recent years, the focus in chemistry has kept expanding from targeting small binding pockets in proteins to recognizing patches on protein surfaces, mostly via supramolecular chemistry, with the goal to modulate protein–protein interactions. Here we present NMR methods that have been applied to characterize these molecular interactions and discuss the challenges of this endeavor.

Highlights

In recent years, the focus of biochemical research and drug development has shifted from the inhibition of single enzymes to targeting protein-protein interactions [1,2], which play key roles in cellular function and dysfunction [3,4]
Protein-based solution NMR spectroscopy has long been the method of choice to map ligand binding sites at atomic resolution
With the recent improvements like fast acquisition techniques, selective isotope labeling of single or multiple types of amino acid residues or side chain specific spectra, NMR continues to thrive in the growing field of targeting protein surfaces with supramolecular chemistry

Summary

Introduction

The focus of biochemical research and drug development has shifted from the inhibition of single enzymes to targeting protein-protein interactions [1,2], which play key roles in cellular function and dysfunction [3,4]. Ligands designed to recognize positively charged regions, containing lysine (Lys) and arginine (Arg) residues, on a protein include supramolecular tweezers [5,6,7,8,9,10,11,12,13,14,15,16,17,18] as well as sulfonatoand phosphonato-calixarenes [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. While steric accessibility is an important determining factor for calixarene binding, the overall local electrostatic potential of the protein surface as well as other non-covalent interactions such as hydrophobic interactions or aromatic ring stacking contribute to a certain selectivity for some lysine residues over others as well.

Results

Conclusion