Using Enhanced Sampling Simulations to Study the Conformational Space of Chiral Aromatic Peptoid Monomers

Peptoids, or N-substituted glycines, are peptide-like
materials
that form a wide variety of secondary structures owing to their enhanced
flexibility and a diverse collection of possible side chains. Compared
to that of peptides, peptoids have a substantially more complex conformational
landscape. This is mainly due to the ability of the peptoid amide
bond to exist in both cis- and trans-conformations. This makes conventional molecular dynamics simulations
and even some enhanced sampling approaches unable to sample the complete
energy landscapes. In this article, we present an extension to the
CGenFF-NTOID peptoid atomistic forcefield by adding parameters for
four side chains to the previously available collection. We employ
explicit solvent well-tempered metadynamics simulations to optimize
our forcefield parameters and parallel bias metadynamics to study
the cis–trans isomerism for
SN1-phenylethyl (s1pe) and SN1-naphthylethyl (s1ne) peptoid monomers, the free energy minima generated from which are
validated with available experimental data. In the absence of experimental
data, we supported our atomistic simulations with ab initio calculations. This work represents an important step toward the
computational design of peptoid-based materials.