Poster De Conférence Année : 2023

Molecular Dynamics with Orientational Constraints to investigate the conformational landscape of biomolecules

Résumé

In both bio(macro)molecules and small molecules, structure and dynamics conspire to create molecular conformational landscapes. Mapping this landscape is crucial towards understanding the molecular mechanisms behind their functional properties (1). Anisotropic NMR data, such as residual dipolar couplings (RDCs), are exquisitely sensitive to both structure and dynamics occurring on the ps- ms timescales. In the presence of flexibility, however, the translation of RDCs into conformational information has traditionally not been straightforward. Recently, Molecular Dynamics simulations with Orientational Constraints (MDOC) have been proposed (2, 3) as a means to achieve this. The use of RDCs as orientational constraints should allow to accelerate the MD simulation up to ms timescale motions, allowing the quantification and visualization of complex long timescale dynamics (2, 3). Here, we explore the use of MDOC simulations with RDCs as experimental restraints to describe the conformational landscape of biomolecules. To test the potential of the method, we first investigated isopinocampheol and a trisaccharide raffinose, two small molecules with different degrees of flexibility. In each case, we present MDOC simulations with a rich dataset of RDCs used as orientational constraints, including long-range 1H-1H and 13C-1H RDCs (4). We will also show some preliminary results on a disordered peptide sequence derived from non-structural protein 5A of Hepatitis C Virus, whose conformational landscape is relevant for understanding its viral replication machinery (5). The RDC-restrained MDOC simulations will provide insight on the accessible states by the (macro)molecules, allowing for a thorough verification of their conformational landscapes with underlying fluctuations occurring on ps to ms timescales. References: 1. Ringkjobing Jensen M., et al., Chemical Reviews 114 (2014) 6632-6660 2. Di Pietro M. E., et al., Journal of Physical Chemistry B 123 (2019) 8480–8491 3. Tzvetkova P., et al., Chemical Science 10 (2019) 8774–8791 4. Sinnaeve D., et al., Angewandte Chemie 59 (2020) 5316-5320 5. Dujardin M., et al., Journal of Biological Chemistry 294 (2019) 13171-13185

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Dates et versions

hal-05017701 , version 1 (02-04-2025)

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  • HAL Id : hal-05017701 , version 1

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Wiktor Adamski, Xavier Hanoulle, Davy Sinnaeve. Molecular Dynamics with Orientational Constraints to investigate the conformational landscape of biomolecules. XIIIth International Conference — NMR: a tool for biology, May 2023, Paris, France. ⟨hal-05017701⟩
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