(326f) Exploration of Tertiary Structure in Sequence-Defined Polymers Using Molecular Dynamics Simulations

Peptoids, or n-substituted glycines, are a class of sequence-defined biomimetic polymers with peptide-like backbones and side chains located on backbone nitrogens rather than alpha carbons. This unique class of materials has been explored for its use in new materials, pharmaceuticals, and catalysis due to increased stability and diversity compared to peptide counterparts [1-2]. Peptoids also demonstrate a strong ability for hierarchical assembly into nanospheres, nanosheets, and tubes, although the molecular driving forces behind these complex assemblies are often not understood [3-4].

Prior experimental work has shown that 15mer peptoid units with disulfide linkages can mimic the helical bundle structure found in proteins by leveraging the chirality-inducing nature of bulky side chains and a hydrophobic core [5]. Despite great progress in this area from the experimental perspective, there are still significant gaps in our understanding of the atomic and nanoscale molecular driving forces that give rise to particular folds and stabilize sequences with tertiary structure. In this presentation, we present a molecular dynamics (MD) study on the folding behavior of these sequence-specific polymers into such tertiary structures. After presenting the methodology for using ensembles of classical MD simulations to evaluate peptoid folding stability, we then discuss key features of a stable helical hairpin that promote stability in water. Finally, we discuss a comparative study on different sequences with known differences in folding stability.

[1] T. Dohm, M., Kapoor, R., & E. Barron, A. (2011). Peptoids: Bio-inspired polymers as Potential Pharmaceuticals. Current Pharmaceutical Design, 17(25), 2732–2747. https://doi.org/10.2174/138161211797416066

[2] Maayan, G., Ward, M. D., & Kirshenbaum, K. (2009). Folded biomimetic oligomers for enantioselective catalysis. Proceedings of the National Academy of Sciences, 106(33), 13679–13684. doi: 10.1073/pnas.0903187106

[3] Robertson, E. J., Battigelli, A., Proulx, C., Mannige, R. V., Haxton, T. K., Yun, L., Whitelam, S., & Zuckermann, R. N. (2016). Design, synthesis, assembly, and engineering of Peptoid nanosheets. Accounts of Chemical Research, 49(3), 379–389. https://doi.org/10.1021/acs.accounts.5b00439

[4] Li, Z., Cai, B., Yang, W., & Chen, C.-L. (2021). Hierarchical nanomaterials assembled from peptoids and other sequence-defined synthetic polymers. Chemical Reviews, 121(22), 14031–14087. https://doi.org/10.1021/acs.chemrev.1c00024

[5] Lee, B.-C., Zuckermann, R. N., & Dill, K. A. (2005). Folding a nonbiological polymer into a compact multihelical structure. Journal of the American Chemical Society, 127(31), 10999–11009. https://doi.org/10.1021/ja0514904