Self-binding peptides: Binding-upon-folding versus folding-upon-binding
Abstract
Self-binding peptide (SBP) represents a novel biomolecular phenomenon spanning between folding and binding. It is a structurally independent, short peptide segment within a monomeric protein and fulfills biological function by dynamically binding to/unbinding from its target domain in the same monomer. Here, four representative SBP systems, including mouse proto-oncogene Vav, human retinoic acid receptor RARγ, fruit fly scaffold module INAD and crypto 14-3-3 protein Cp14b, are investigated systematically by using atomistic molecular dynamics (MD) simulations and post binding energetics analyses. The native bound structure, artificial unbound state and isolated peptide segment of SBP moieties in the four systems were constructed, analyzed and compared in detail. It is revealed that the SBP interaction with their targets is almost a binding phenomenon at single-molecule level, but presence of a polypeptide linker between the SBP and target can promote the binding efficiency since the linker restriction largely increases the probability of SBP-target encounters in a statistical physics point of view. In this respect, unlike classical peptide-mediated interactions where the intrinsically disordered peptides are folded into an ordered structure upon binding to their protein partners (folding-upon-binding), we herein propose SBPs as a new and reversed biological event that is naturally a folding phenomenon but exhibits a typical binding behavior (binding-upon-folding).
- Publication:
-
Journal of Theoretical Biology
- Pub Date:
- May 2019
- DOI:
- 10.1016/j.jtbi.2019.02.014
- Bibcode:
- 2019JThBi.469...25L
- Keywords:
-
- Biomolecular phenomenon;
- Molecular recognition;
- Peptide-domain interaction;
- Intrinsic disorder;
- Peptide flexibility;
- Computational peptidology