Effects of Cyclization on Peptide Backbone Dynamics

Wang, Conan K., Swedberg, Joakim E., Northfield, Susan E. and Craik, David J. (2015) Effects of Cyclization on Peptide Backbone Dynamics. Journal of Physical Chemistry B, 119 52: 15821-15830. doi:10.1021/acs.jpcb.5b11085

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Author Wang, Conan K.
Swedberg, Joakim E.
Northfield, Susan E.
Craik, David J.
Title Effects of Cyclization on Peptide Backbone Dynamics
Journal name Journal of Physical Chemistry B   Check publisher's open access policy
ISSN 1520-5207
Publication date 2015-12-31
Year available 2015
Sub-type Article (original research)
DOI 10.1021/acs.jpcb.5b11085
Open Access Status File (Author Post-print)
Volume 119
Issue 52
Start page 15821
End page 15830
Total pages 10
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Abstract Despite the widespread use of cyclization as a structure optimization tool in peptide chemistry, little is known about the effect of cyclization on peptide internal dynamics. In this work, we used a combination of multifield NMR relaxation and molecular dynamics techniques to study both monocyclic and polycyclic peptides that have promising biopharmaceutical properties, namely, VH, SFTI-1, and cVc1.1, and their less constrained analogues to study the effects of backbone cyclization (which forms a macrocycle) and disulfide-bond cyclization (which forms internal cycles). We confirmed that backbone cyclization contributes to the rigidity of the monocyclic VH. Interestingly, however, backbone cyclization of the bicyclic SFTI-1 had a limited effect on rigidity, with changes in internal dynamics localized around the ligation site. This suggests that the disulfide bond, which creates an internal cycle, has an insulating effect, protecting the internal cycle from external motional effects. An insulating effect was also observed for the polycyclic cVc1.1: The rigidity of the core was not enhanced by macrocyclization. Additionally, we found that disulfide bonds provide a greater contribution to overall rigidity than macrocyclization. Overall, our results suggest that, although backbone cyclization can improve rigidity, there is a complex interplay between dynamics and cyclization, particularly for polycyclic systems.
Keyword Chemistry, Physical
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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