A rotamer library to enable modeling and design of peptoid foldamers

J Am Chem Soc. 2014 Jun 18;136(24):8772-82. doi: 10.1021/ja503776z. Epub 2014 Jun 9.

Abstract

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 quantum mechanics (QM) and/or molecular mechanics (MM) energy calculations to identify side-chain rotamers. We show by comparison to experimental peptoid structures that both methods provide an accurate prediction of peptoid side chain placements in folded peptoid oligomers and at protein interfaces. We have incorporated our peptoid rotamer libraries into ROSETTA, a molecular design package previously validated in the context of protein design and structure prediction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Models, Molecular*
  • Molecular Structure
  • Peptide Library*
  • Peptoids / chemistry*
  • Protein Folding*
  • Quantum Theory

Substances

  • Peptide Library
  • Peptoids