Insights into How Cyclic Peptides Switch Conformations

Cyclic peptides have recently emerged as promising modulators of protein–protein interactions. However, it is currently highly difficult to predict the structures of cyclic peptides owing to their rugged conformational free energy landscape, which prevents sampling of all thermodynamically relevant...

Full description

Saved in:
Bibliographic Details
Published in:Journal of chemical theory and computation 2016-05, Vol.12 (5), p.2480-2488
Main Authors: McHugh, Sean M, Rogers, Julia R, Yu, Hongtao, Lin, Yu-Shan
Format: Article
Language:English
Subjects:
Coherence
Computer simulation
Free energy
Landscapes
Modulators
Molecular Dynamics Simulation
Peptides
Peptides, Cyclic - chemistry
Protein Conformation
Sampling
Switches
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cyclic peptides have recently emerged as promising modulators of protein–protein interactions. However, it is currently highly difficult to predict the structures of cyclic peptides owing to their rugged conformational free energy landscape, which prevents sampling of all thermodynamically relevant conformations. In this article, we first investigate how a relatively flexible cyclic hexapeptide switches conformations. It is found that, although the circular geometry of small cyclic peptides of size 6–8 may require rare, coherent dihedral changes to sample a new conformation, the changes are rather local, involving simultaneous changes of ϕ i and ψ i or ψ i and ϕ i+1. The understanding of how these cyclic peptides switch conformations enables the use of metadynamics simulations with reaction coordinates specifically targeting such coupled two-dihedral changes to effectively sample cyclic peptide conformational space.
ISSN:1549-9618
1549-9626
DOI:10.1021/acs.jctc.6b00193