Peptoids (N-substituted oligoglycines) are a class of peptidomimetics that demonstrate the ability to fold into stable, well-defined conformations. Peptoid chains are cheap and easy to synthesize, have high temperature stability and are not degraded by proteases. Peptoid residues can have arbitrary sidechains, bridging the realm between small-molecule and peptide inhibitors, as well as providing a framework ideal for designing versatile protein-protein inhibitors that mimic a peptide substrate. A challenging aspect of designing peptoid foldamers is the lack of backbone hydrogen bonding, and the greater propensity for the amide bond to assume the cis configuration. Peptoids with bulky chiral sidechains, however, can form stable cis-amide helices primarily driven by steric packing. In an effort to advance computational design of peptoids, our group has systematically evaluated all-purpose forcefields such as GAFF (General Amber Forcefield) using replica exchange molecular dynamics (REMD) simulations, and found it to incorrectly reproduce backbone structural propensities for Nspe and Ns1npe residues. To remedy this, we have developed a modified phi-angle backbone potential that shows increased helix stability and better agreement with both QM calculations and experimental solution NMR data. We discuss applications of our improved potentials towards several ongoing peptoid design projects.

Improved backbone parameters for peptoid modeling

248th National Meeting (2014)

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