Characterization of Heparin’s Conformational Ensemble by Molecular Dynamics Simulations and Nuclear Magnetic Resonance Spectroscopy

Janke, J. Joel; Yu, Yanlei; Pomin, Vitor H.; Zhao, Jing; Wang, Chunyu; Linhardt, Robert J.; García, Angel Enrique

doi:10.1021/acs.jctc.1c00760

Title: Characterization of Heparin’s Conformational Ensemble by Molecular Dynamics Simulations and Nuclear Magnetic Resonance Spectroscopy

Journal Article · 02 February 2022 · Journal of Chemical Theory and Computation

DOI: https://doi.org/10.1021/acs.jctc.1c00760 · OSTI ID:1844154

Janke, J. Joel ^[1]; Yu, Yanlei ^[1]; Pomin, Vitor H. ^[2]; Zhao, Jing ^[1];

^[1];

^[3]

Rensselaer Polytechnic Inst., Troy, NY (United States)
Univ. of Mississippi, Oxford, MS (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

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. In this work, 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.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Laboratory Directed Research and Development (LDRD) Program

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 1844154

Report Number(s):: LA-UR-20-28381

Journal Information:: Journal of Chemical Theory and Computation, Journal Name: Journal of Chemical Theory and Computation Journal Issue: 3 Vol. 18; ISSN 1549-9618

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
ArixtraTM
Biological Science
CHARMM36
GLYCAM06
Glycosaminoglycans
Molecular dynamics simulations

Title: Characterization of Heparin’s Conformational Ensemble by Molecular Dynamics Simulations and Nuclear Magnetic Resonance Spectroscopy

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