(660c) Development of an Atomistic Forcefield for Peptoids

Peptoids, or poly N-substituted glycines, are synthetic biocompatible peptidomimetics that have been used to develop antimicrobial agents, lung surfactants and drug delivery vehicles. They are protease resistant and have enhanced cellular uptake, which makes them attractive candidates for biological applications. Since peptoids lack native backbone hydrogens connected to an electronegative atom and hence have no backbone hydrogen bonding, their secondary structure is governed primarily by steric interactions (in the absence of specific interactions between side chains). Furthermore, unlike peptides, which have the trans configuration as the prevalent amide bond isomer, peptoid amide bonds can have both cis- and trans- configurations. This allows for peptoids to exhibit a variety of secondary structures that are not observed in peptides.

Due to these differences and the varied accessible secondary structures between peptoids and peptides, force fields fitted for peptides have very limited applicability for peptoids. Weiser and Santiso [1] recently developed an atomistic force field for peptoids NTOID, which is based on CGenFF. NTOID has the capability to model peptoids with amide bonds in both the cis- and trans- conformation for three different sidechain residues: sarcosine, 1-phenylmethyl and 1-phenylethyl. In this work, we present an extension of this approach where we increase the applicability of the NTOID model to more peptoid sidechains.

The sidechains that were determined as prospective candidates for parameter fitting are N-(methoxyethyl) glycine and (S)-N-(1-naphthylethyl) glycine. We arrived at these sidechains after using an online utility known as the Peptoid Data Bank [2], which stores experimental structural and XRD crystallographic data for peptoids. Using an application of this utility that ranks residues based on the number of papers published that focus on them, we decided on these two residues. The parameters for these sidechains were optimized using enhanced sampling simulations in the software package NAMD while fitting to the handedness preferences experimentally observed in solution. These new forcefield parameters, coupled with the 3 already fitted sidechains, allow us to study a large number of polypeptoid chains through simulations and analyze the secondary structures and the associated folding mechanisms.

References

[1] Laura J. Weiser and Erik E. Santiso, “A CGenFF-based force field for simulations of peptoids with both cis and trans peptide bonds”, Journal of Computational Chemistry, 2019, 40(22), 1946-1956.

[2] Peptoid Data Bank (https://www.databank.peptoids.org/home)