Evaluating the Conformations and Dynamics of Peptoid Macrocycles

James R.B. Eastwood, Linhai Jiang, Richard Bonneau, Kent Kirshenbaum, P. Douglas Renfrew

Research output: Contribution to journalArticlepeer-review


Peptoid macrocycles are versatile and chemically diverse peptidomimetic oligomers. However, the conformations and dynamics of these macrocycles have not been evaluated comprehensively and require extensive further investigation. Recent studies indicate that two degrees of freedom, and four distinct conformations, adequately describe the behavior of each monomer backbone unit in most peptoid oligomers. On the basis of this insight, we conducted molecular dynamics simulations of model macrocycles using an exhaustive set of idealized possible starting conformations. Simulations of various sizes of peptoid macrocycles yielded a limited set of populated conformations. In addition to reproducing all relevant experimentally determined conformations, the simulations accurately predicted a cyclo-octamer conformation for which we now present the first experimental observation. Sets of three adjacent dihedral angles (φi, ψi, ωi+1) exhibited correlated crankshaft motions over the course of simulation for peptoid macrocycles of six residues and larger. These correlated motions may occur in the form of an inversion of one amide bond and the concerted rotation of the preceding φ and ψ angles to their mirror-image conformation, a variation on "crankshaft flip"motions studied in polymers and peptides. The energy landscape of these peptoid macrocycles can be described as a network of conformations interconnected by transformations of individual crankshaft flips. For macrocycles of up to eight residues, our mapping of the landscape is essentially complete.

Original languageEnglish (US)
Pages (from-to)5161-5174
Number of pages14
JournalJournal of Physical Chemistry B
Issue number28
StatePublished - Jul 21 2022


  • Amides
  • Molecular Conformation
  • Molecular Dynamics Simulation
  • Peptides/chemistry
  • Peptoids/chemistry

ASJC Scopus subject areas

  • Materials Chemistry
  • Surfaces, Coatings and Films
  • Physical and Theoretical Chemistry


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