Peptoids are a family of synthetic oligomers composed of N-substituted glycine units. Along with other “foldamer” systems, peptoid oligomer sequences can be predictably designed to form a variety of stable secondary structures. It is not yet evident if foldamer design can be extended to reliably create tertiary structure features that mimic more complex biomolecular folds and functions. Computational modeling and prediction of peptoid conformations will likely play a critical role in enabling complex biomimetic designs. We introduce a computational approach to provide accurate conformational and energetic parameters for peptoid side chains needed for successful modeling and design. We find that peptoids can be described by a “rotamer” treatment, similar to that established for proteins, in which the peptoid side chains display rotational isomerism to populate discrete regions of the conformational landscape. Because of the insufficient number of solved peptoid structures, we have calculated the relative energies of side-chain conformational states to provide a backbone-dependent(BBD) rotamer library for a set of 54 different peptoid side chains.We evaluated two rotamer library development methods that employ quantummechanics (QM) and/or molecular mechanics (MM) energy calculationsto identify side-chain rotamers. We show by comparison to experimentalpeptoid structures that both methods provide an accurate predictionof peptoid side chain placements in folded peptoid oligomers and atprotein interfaces. We have incorporated our peptoid rotamer librariesinto ROSETTA, a molecular design package previously validated in thecontext of protein design and structure prediction.
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