Peptide binding to a PDZ domain by electrostatic steering via nonnative salt bridges

TitlePeptide binding to a PDZ domain by electrostatic steering via nonnative salt bridges
Publication TypeJournal Article
Year of Publication2015
AuthorsBlöchliger N., Xu M., Caflisch A.
JournalBiophysical Journal
Volume108
Issue9
Pagination2362-2370
Date Published2015 May 5
Type of ArticleResearch Article
ISSN1542-0086
Keywordsbinding, electrostatic steering, electrostatics, Encounter complex, molecular dynamics, Peptides, SAPPHIRE plot
Abstract

We have captured the binding of a peptide to a PDZ domain by unbiased molecular dynamics simulations. Analysis of the trajectories reveals on-pathway encounter complex formation, which is driven by electrostatic interactions between negatively charged carboxylate groups in the peptide and positively charged side chains surrounding the binding site. In contrast, the final stereospecific complex, which matches the crystal structure, features completely different interactions, namely the burial of the hydrophobic side chain of the peptide C-terminal residue and backbone hydrogen bonds. The simulations show that nonnative salt bridges stabilize kinetically the encounter complex during binding. Unbinding follows the inverse sequence of events with the same nonnative salt bridges in the encounter complex. Thus, in contrast to protein folding, which is driven by native interactions, the binding of charged peptides can be steered by nonnative interactions, which might be a general mechanism, e.g., in the recognition of histone tails by bromodomains.

DOI10.1016/j.bpj.2015.03.038
pubindex

0198

Alternate JournalBiophys. J.
PubMed ID25954893
PubMed Central IDPMC4423040
Highlight Role: 
Molecular Interactions