Cargando…

Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide

Understanding structural transitions within macromolecules remains an important challenge in biochemistry, with important implications for drug development and medicine. Insight into molecular behavior often requires residue-specific dynamics measurement at micromolar concentrations. We studied MP01...

Descripción completa

Detalles Bibliográficos
Autores principales: Lindemann, William R., Evans, Ethan D., Mijalis, Alexander J., Saouaf, Olivia M., Pentelute, Bradley L., Ortony, Julia H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018720/
https://www.ncbi.nlm.nih.gov/pubmed/32054898
http://dx.doi.org/10.1038/s41598-020-59047-7
_version_ 1783497378289942528
author Lindemann, William R.
Evans, Ethan D.
Mijalis, Alexander J.
Saouaf, Olivia M.
Pentelute, Bradley L.
Ortony, Julia H.
author_facet Lindemann, William R.
Evans, Ethan D.
Mijalis, Alexander J.
Saouaf, Olivia M.
Pentelute, Bradley L.
Ortony, Julia H.
author_sort Lindemann, William R.
collection PubMed
description Understanding structural transitions within macromolecules remains an important challenge in biochemistry, with important implications for drug development and medicine. Insight into molecular behavior often requires residue-specific dynamics measurement at micromolar concentrations. We studied MP01-Gen4, a library peptide selected to rapidly undergo bioconjugation, by using electron paramagnetic resonance (EPR) to measure conformational dynamics. We mapped the dynamics of MP01-Gen4 with residue-specificity and identified the regions involved in a structural transformation related to the conjugation reaction. Upon reaction, the conformational dynamics of residues near the termini slow significantly more than central residues, indicating that the reaction induces a structural transition far from the reaction site. Arrhenius analysis demonstrates a nearly threefold decrease in the activation energy of conformational diffusion upon reaction (8.0 k(B)T to 3.4 k(B)T), which occurs across the entire peptide, independently of residue position. This novel approach to EPR spectral analysis provides insight into the positional extent of disorder and the nature of the energy landscape of a highly reactive, intrinsically disordered library peptide before and after conjugation.
format Online
Article
Text
id pubmed-7018720
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-70187202020-02-21 Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide Lindemann, William R. Evans, Ethan D. Mijalis, Alexander J. Saouaf, Olivia M. Pentelute, Bradley L. Ortony, Julia H. Sci Rep Article Understanding structural transitions within macromolecules remains an important challenge in biochemistry, with important implications for drug development and medicine. Insight into molecular behavior often requires residue-specific dynamics measurement at micromolar concentrations. We studied MP01-Gen4, a library peptide selected to rapidly undergo bioconjugation, by using electron paramagnetic resonance (EPR) to measure conformational dynamics. We mapped the dynamics of MP01-Gen4 with residue-specificity and identified the regions involved in a structural transformation related to the conjugation reaction. Upon reaction, the conformational dynamics of residues near the termini slow significantly more than central residues, indicating that the reaction induces a structural transition far from the reaction site. Arrhenius analysis demonstrates a nearly threefold decrease in the activation energy of conformational diffusion upon reaction (8.0 k(B)T to 3.4 k(B)T), which occurs across the entire peptide, independently of residue position. This novel approach to EPR spectral analysis provides insight into the positional extent of disorder and the nature of the energy landscape of a highly reactive, intrinsically disordered library peptide before and after conjugation. Nature Publishing Group UK 2020-02-13 /pmc/articles/PMC7018720/ /pubmed/32054898 http://dx.doi.org/10.1038/s41598-020-59047-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lindemann, William R.
Evans, Ethan D.
Mijalis, Alexander J.
Saouaf, Olivia M.
Pentelute, Bradley L.
Ortony, Julia H.
Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide
title Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide
title_full Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide
title_fullStr Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide
title_full_unstemmed Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide
title_short Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide
title_sort quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018720/
https://www.ncbi.nlm.nih.gov/pubmed/32054898
http://dx.doi.org/10.1038/s41598-020-59047-7
work_keys_str_mv AT lindemannwilliamr quantifyingresiduespecificconformationaldynamicsofahighlyreactive29merpeptide
AT evansethand quantifyingresiduespecificconformationaldynamicsofahighlyreactive29merpeptide
AT mijalisalexanderj quantifyingresiduespecificconformationaldynamicsofahighlyreactive29merpeptide
AT saouafoliviam quantifyingresiduespecificconformationaldynamicsofahighlyreactive29merpeptide
AT pentelutebradleyl quantifyingresiduespecificconformationaldynamicsofahighlyreactive29merpeptide
AT ortonyjuliah quantifyingresiduespecificconformationaldynamicsofahighlyreactive29merpeptide