(588i) Exploration of the Secondary Structure Peptoid Folding Landscape with Metadynamics

Peptoids, or n-substitued glycines, are increasingly stable but complex and diverse oligomeric structures which have been explored for a number of biomimetic applications including drug molecules, surfactants of catalysts.^1-2 In contrast to their peptide counterparts, on peptoids the sidechain is located on the backbone nitrogen resulting in a flexible omega backbone dihedral that can isomerize into both stable cis- and trans- backbone conformations. This unique feature of peptoids allows for these structures to span a large design space of chemical and structural functionality through the careful tuning of their side chains. One novel example of this is the N-substituted α-chiral aromatic (S)-N-(1-phenylethyl)glycine (Nspe) oligomers which can produce stable helical structures in both aqueous and non-aqueous solutions.³ Further, many of these oligomers have been shown to have the capacity to assemble into more complex hierarchical assemblies like microspheres, nanosheets, and dynamic single-walled nanotube structures. However, little is known about the molecular-level mechanisms that drive these assemblies.

Enhanced sampling molecular dynamics approaches provide an opportunity to understand this dynamic behavior at an atomistic level of detail, giving insight into the complex energetic landscape of the elusive peptoid backbone. Parallel biased metadynamics is one such method that can be used to sample highly dimensional systems. Here we present our application of parallel tempering parallel bias metadynamics in the well-tempered ensemble (PTPBMetaD-WTE), which overcomes sampling limitations related to the flexible peptoid backbone, to sample the 12-dimensional energetic landscape for a range of different peptoid chemistries and chain lengths. From this, we can begin to interpret the energetic and entropic mechanisms that give rise to these unique complex assemblies for a number of different peptoid chemistries.

References

[1] Dohm MT, Kapoor R, Barron AE. Peptoids: Bio-Inspired Polymers as Potential Pharmaceuticals. Curr. Pharm. 2011, 47 (17), 2732.

[2] Maayan G, Ward MD, Kirshenbaum K. Folded biomimetic oligomers for enantioselective catalysis. Proc Natl Acad Sci 2019, 106(33):13679-84.

[3] Wu C, Sanborn S, Huang K, Zuckermann RN, Barron AE. Peptoid Oligomers with α-Chiral, Aromatic Side Chains: Sequence Requirements for the Formation of Stable Peptoid Helices. J. Am. Chem. Soc. 2001, 123, 28, 6778-6784.