Studying Peptoid Side-Chain/Structure Relationships Using Metadynamics and the Generalized Charmm Force Field

Peptoids (poly-n-substituted glycines) are peptide-like macromolecules composed of modified glycine units which have side chains attached to the nitrogen atoms. Peptoids are biocompatible, resistant to protease degradation, and they can be synthesized using more than 300 commercially available amines, making peptoids versatile and appealing compounds for combinatorial materials design. Applications for peptoids include antimicrobial coatings, binding inhibitors, drug carriers, and lung surfactants.

We have previously fit peptoid-specific parameters to for the CHARMM General Force Field (CGENFF). We briefly describe the important considerations to observe when fitting peptoid parameters with CHARMM. Finally, we show the effectiveness of these CGENFF peptoid parameters in reproducing experimentally observed peptoid structures.

We present molecular simulation studies of the relationship between peptoid side chains and the peptoid backbone folding. We show the results of atomistic molecular dynamics simulations, Well-Tempered Metadynamics, and Bias Exchange Metadynamics that explore the free energy surfaces of peptoid dimers and short peptoid chains. Finally, we suggest new combinations of peptoid side chains and offer predictions on their backbone structure.

This work presents a framework for studying peptoid side-chain/structure relationships at the atomistic level using a CHARMM based force-field. In the near future, the methods here will be combined with additional NMR studies to study novel, non-protein-like peptoid side chains and their effect on peptoid backbone conformations.