Thermodynamic Basis for the Stabilization of Helical Peptoids by Chiral Sidechains

Alamdari, Sarah; Torkelson, Kaylyn; Wang, Xiaoqian; Chen, Chun-Long; Ferguson, Andrew L.; Pfaendtner, Jim

doi:10.1021/acs.jpcb.3c01913

Title: Thermodynamic Basis for the Stabilization of Helical Peptoids by Chiral Sidechains

Journal Article · Wed Jun 28 00:00:00 EDT 2023 · Journal of Physical Chemistry. B

DOI:https://doi.org/10.1021/acs.jpcb.3c01913· OSTI ID:2202416

^[1]; Torkelson, Kaylyn ^[1]; Wang, Xiaoqian ^[1];

^[2];

^[3];

^[4]

University of Washington, Seattle, WA (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); University of Washington, Seattle, WA (United States)
University of Chicago, IL (United States)
University of Washington, Seattle, WA (United States); Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Peptoids are a class of highly customizable biomimetic foldamers that retain properties from both proteins and polymers. It has been shown that peptoids can adopt peptide-like secondary structures through the careful selection of sidechain chemistries, but the underlying conformational landscapes that drive these assemblies at the molecular level remain poorly understood. Given the high flexibility of the peptoid backbone, it is essential that methods applied to study peptoid secondary structure formation possess the requisite sensitivity to discriminate between structurally similar yet energetically distinct microstates. In this work, a generalizable simulation scheme is used to robustly sample the complex folding landscape of various 12mer polypeptoids, resulting in a predictive model that links sidechain chemistry with preferential assembly into one of 12 accessible backbone motifs. Using a variant of the metadynamics sampling method, four peptoid dodecamers are simulated in water: sarcosine, N-(1-phenylmethyl)glycine (Npm), (S)-N-(1-phenylethyl)glycine (Nspe), and (R)-N-(1-phenylethyl)glycine (Nrpe)–to determine the underlying entropic and energetic impacts of hydrophobic and chiral peptoid sidechains on secondary structure formation. Our results indicate that the driving forces to assemble Nrpe and Nspe sequences into polyproline type-I helices in water are found to be enthalpically driven, with small benefits from an entropic gain for isomerization and steric strain due to the presence of the chiral center. The minor entropic gains from bulky chiral sidechains in Nrpe- and Nspe-containing peptoids can be explained through increased configurational entropy in the cis state. However, overall assembly into a helix is found to be overall entropically unfavorable. Furthermore, these results highlight the importance of considering the many various competing interactions in the rational design of peptoid secondary structure building blocks.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); Energy Frontier Research Centers (EFRC) (United States). The Center for the Science of Synthesis Across Scales (CSSAS); Univ. of Washington, Seattle, WA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF)

Grant/Contract Number:: AC05-76RL01830; SC0019288; DGE-1762114

OSTI ID:: 2202416

Alternate ID(s):: OSTI ID: 1993123

Report Number(s):: PNNL-SA-186010

Journal Information:: Journal of Physical Chemistry. B, Vol. 127, Issue 27; ISSN 1520-6106

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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