Abstract
Peptide nanodiscs are promising anti-atherosclerosis therapeutics, drug delivery particles and structural biology tools. However, the lack of experimental methods for structural and dynamical characterization of these particles hinders their further development. Here, we integrated nuclear magnetic resonance (NMR), small-angle x-ray scattering, and small-angle neutron scattering experiments with molecular dynamics (MD) simulations to investigate the structure and dynamics of peptide nanodiscs stabilized by the apolipoprotein A-I mimetic peptide 22 A with therapeutic activity against atherosclerosis. This multi-technique approach takes advantage of combining average size and shape information from small-angle scattering, peptide site-specific information from NMR spectroscopy, and interpretative power of MD simulations. Our results reveal the intrinsic polydispersity in the size of peptide nanodiscs. Our consensus model suggests that 22 A peptides are predominantly in α-helical configuration with a disordered inter-helical orientation around the lipid matrix. The terminal regions of the peptides display greater flexibility relative to the peptide core and an enhanced C-terminal exposure to solvent, which could facilitate interaction with the enzyme LCAT. The methodological approach described in this paper paves the way for the design of more stable and effective therapeutic nanodiscs and for the characterization of other biomolecular aggregates that are beyond the scope of current structural biology techniques.
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Data availability
Molecular dynamics data and NMR spectra are available at https://zenodo.org/doi/10.5281/zenodo.18773356. All other relevant data are available upon request from the corresponding authors.
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Acknowledgements
We acknowledge the European Synchrotron Radiation Facility (ESRF) for provision of synchrotron radiation facilities under proposal number MX-2582 and we would like to thank Mark Tully for assistance and support in using beamline BM29. We acknowledge the Institut Laue-Langevin (ILL) for provision of neutron radiation facilities, and we would like to thank Anne Martel for assistance and support in using beamline D22. The facilities and expertise of the HiLIFE NMR unit at the University of Helsinki, a member of Instruct-ERIC Centre Finland, FINStruct, and Biocenter Finland are gratefully acknowledged. We acknowledge CSC – IT Center for Science for computational resources. This work was supported by The Academy of Finland [grant numbers 315596, 350636, 353815, 356568].
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S.I.V., R.N., and T.N. performed the NMR assignment. S.N performed and analyzed NMR and SAS experiments. A.N., R.N., and G.K performed and analyzed MD simulations. S.N, A.N., R.N., O.H.S.O., and A.K. wrote the manuscript. O.H.S.O. and A.K. conceptualized and supervised the work.
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Communications Chemistry thanks Bankala Krishnarjuna, Evgeniy S. Salnikov and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Nouri, S., Niemelä, A., Nencini, R. et al. Exploring the structure and dynamics of peptide nanodiscs through a synergistic approach with NMR spectroscopy, SAS and MD simulations. Commun Chem (2026). https://doi.org/10.1038/s42004-026-02015-5
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DOI: https://doi.org/10.1038/s42004-026-02015-5