Characterization of heparin’s conformational ensemble by molecular dynamics simulations and nuclear magnetic resonance spectroscopy
Authors
Janke, J.J.
Yu, Y.
Pomin, Vitor H.
Zhao, J.
Wang, C.
Linhardt, Robert J.
García, A.E.
ORCID
https://orcid.org/0000-0003-2219-5833
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Other Contributors
Issue Date
2022-03-08
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
Degree
Terms of Use
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Full Citation
Characterization of heparin’s conformational ensemble by molecular dynamics simulations and nuclear magnetic resonance spectroscopy, J. J. Janke, Y. Yu, V. H. Pomin, J. Zhao, C. Wang, R. J. Linhardt, A. E. García, Journal of Chemical Theory and Computation, 18, 1894-1904, 2022.
Abstract
Heparin is a highly charged, polysulfated polysaccharide and serves as an anticoagulant. Heparin binds to multiple proteins throughout the body, suggesting a large range of potential therapeutic applications. Although its function has been characterized in multiple physiological contexts, heparin’s solution conformational dynamics and structure–function relationships are not fully understood. Molecular dynamics (MD) simulations facilitate the analysis of a molecule’s underlying conformational ensemble, which then provides important information necessary for understanding structure–function relationships. However, for MD simulations to afford meaningful results, they must both provide adequate sampling and accurately represent the energy properties of a molecule. The aim of this study is to compare heparin’s conformational ensemble using two well-developed force fields for carbohydrates, known as GLYCAM06 and CHARMM36, using replica exchange molecular dynamics (REMD) simulations, and to validate these results with NMR experiments. The anticoagulant sequence, an ultra-low-molecular-weight heparin, known as Arixtra (fondaparinux, sodium), was simulated with both parameter sets. The results suggest that GLYCAM06 matches experimental nuclear magnetic resonance three-bond J-coupling values measured for Arixtra better than CHARMM36. In addition, NOESY and ROESY experiments suggest that Arixtra is very flexible in the sub-millisecond time scale and does not adopt a unique structure at 25 C. Moreover, GLYCAM06 affords a much more dynamic conformational ensemble for Arixtra than CHARMM36.
Description
Journal of Chemical Theory and Computation, 18, 1894-1904
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Department
The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
Publisher
American Chemical Society (ACS)
Relationships
The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
Journal of Chemical Theory and Computation
https://harc.rpi.edu/
Rensselaer Polytechnic Institute, Troy, NY
Journal of Chemical Theory and Computation
https://harc.rpi.edu/
Access
A full text version is available in DSpace@RPI