Understanding β-strand mediated protein-protein interactions using peptidomimetics: tuning binding affinity of intrinsically disordered sequences by covalent backbone modification

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Abstract
A significant challenge in chemical biology is to understand and modulate protein-protein interactions (PPIs). Given that many PPIs involve a folded protein domain and a peptide sequence that is intrinsically disordered in isolation, peptides represent powerful tools to understand PPIs and templates for PPI modulator development. Using the interaction between small ubiquitin-like modifiers (SUMO) and SUMO-interacting motifs (SIMs), here we show that N-methylation of the peptide backbone can effectively restrict accessible peptide conformations, predisposing them for protein recognition. Backbone N-methylation in appropriate locations results in faster target binding, and thus higher affinity, as shown by fluorescence anisotropy, relaxation-based NMR experiments, and computational analysis. We show that such higher affinities occur as a consequence of an increase in the energy of the unbound state, and a reduction in the entropic contribution to the binding and activation energies. Thus, backbone N-Methylation may represent a useful modification within the peptidomimetic toolbox to probe β-strand mediated coupled binding and folding interactions.
Funding Information
  • Engineering and Physical Sciences Research Council (EP/N013573/1)
  • Engineering and Physical Sciences Research Council (EP/KO39292/1)
  • Biotechnology and Biological Sciences Research Council (BB/V003577/1)
  • Biotechnology and Biological Sciences Research Council (BB/L01386X/1)
  • Wellcome Trust (223268/Z/21/Z)
  • Engineering and Physical Sciences Research Council (EP/K039202/1)
  • Engineering and Physical Sciences Research Council (EP/K03927X/1)
  • Wellcome Trust (1094950/Z/14/Z)
  • Wellcome Trust (108466/Z/15/Z)

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