Binding of a C-end rule peptide to the neuropilin-1 receptor: a molecular modeling approach

Biochemistry. 2011 Mar 15;50(10):1755-62. doi: 10.1021/bi101662j. Epub 2011 Feb 14.


Neuropilin-1 (NRP-1) is a receptor that plays an essential role in angiogenesis, vascular permeability, and nervous system development. Previous studies have shown that peptides with an N-terminal Arg, especially peptides with the four-residue consensus sequence R/K/XXR/K, bind to NRP-1 cell surfaces. Peptides containing such consensus sequences promote binding and internalization into cells, while blocking the C-terminal Arg (or Lys) prevents the internalization. In this study, we use molecular dynamics simulations to model the structural properties of the NRP-1 complex with a prototypic CendR peptide, RPAR. Our simulations show that RPAR binds NRP-1 through specific interactions of the RPAR C-terminus: three hydrogen bonds and a salt bridge anchor the ligand in the receptor pocket. The modeling results were used as the starting point for a systematic computational study of new RPAR analogues based on chemical modifications of their natural amino acids. Comparison of the structural properties of the new peptide-receptor complexes with the original organization suggests that some of the analogues can increase the binding affinity while reducing the natural sensitivity of RXXR to endogenous proteases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Models, Molecular
  • Neuropilin-1 / chemistry*
  • Neuropilin-1 / metabolism
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Binding
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary


  • Peptides
  • Neuropilin-1