title: Insights into Peptoid Helix Folding Cooperativity from an Improved Backbone Potential.
abstract: Peptoids (N-substituted oligoglycines) are biomimetic polymers that can fold into a variety of unique structural scaffolds. Peptoid helices, which result from the incorporation of bulky chiral side chains, are a key peptoid structural motif whose formation has not yet been accurately modeled in molecular simulations. Here, we report that a simple modification of the backbone φ-angle potential in GAFF is able to produce well-folded cis-amide helices of (S)-N-(1-phenylethyl)glycine (Nspe), consistent with experiment. We validate our results against both QM calculations and NMR experiments. For this latter task, we make quantitative comparisons to sparse NOE data using the Bayesian Inference of Conformational Populations (BICePs) algorithm, a method we have recently developed for this purpose. We then performed extensive REMD simulations of Nspe oligomers as a function of chain length and temperature to probe the molecular forces driving cooperative helix formation. Analysis of simulation data by Lifson-Roig helix-coil theory show that the modified potential predicts much more cooperative folding for Nspe helices. Unlike peptides, per-residue entropy changes for helix nucleation and extension are mostly positive, suggesting that steric bulk provides the main driving force for folding. We expect these results to inform future work aimed at predicting and designing peptoid peptidomimetics and tertiary assemblies of peptoid helices.
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Sudipto
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Guangfeng
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Michel
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Voelz
mesh_terms: D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D034444:Peptoids / Q000737:chemistry*; D017510:Protein Folding; D011789:Quantum Theory
chemical_list: D034444:Peptoids