Designing Well-Structured Cyclic Pentapeptides Based on Sequence–Structure Relationships
Name
nihms980303.pdf
Description
Accepted version
Size
1.37 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Slough, Diana P.
McHugh, Sean M.
Cummings, Ashleigh E.
Dal, Peng
Pentelute, Bradley L.
Kritzer, Joshua A.
Lin, Yu-Shan
Date Issued
March 2018
Journal
The Journal of Physical Chemistry B
Publisher
American Chemical Society (ACS)
Citation
Slough, Diana P. et al. "Designing Well-Structured Cyclic Pentapeptides Based on
Sequence–Structure Relationships." The Journal of Physical Chemistry B 122, 14 (March 2018): 3908-3919 © 2018 American Chemical Society.
Version
Author's final manuscript
Abstract
Cyclic peptides are a promising class of molecules for unique applications. Unfortunately, cyclic peptide design is severely limited by the difficulty in predicting the conformations they will adopt in solution. In this work, we use explicit-solvent molecular dynamics simulations to design well-structured cyclic peptides by studying their sequence-structure relationships. Critical to our approach is an enhanced sampling method that exploits the essential transitional motions of cyclic peptides to efficiently sample their conformational space. We simulated a range of cyclic pentapeptides from all-glycine to a library of cyclo-(X[subscript 1]X[subscript 2]AAA) peptides to map their conformational space and determine cooperative effects of neighboring residues. By combining the results from all cyclo-(X[subscript 1]X[subscript 2]AAA) peptides, we developed a scoring function to predict the structural preferences for X[subscript 1]-X[subscript 2] residues within cyclic pentapeptides. Using this scoring function, we designed a cyclic pentapeptide, cyclo-(GNSRV), predicted to be well structured in aqueous solution. Subsequent circular dichroism and NMR spectroscopy revealed that this cyclic pentapeptide is indeed well structured in water, with a nuclear Overhauser effect and J-coupling values consistent with the predicted structure.
Subjects
Physical and Theoretical Chemistry
Materials Chemistry
Surfaces, Coatings and Films
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/acs.jpcb.8b01747
