(465e) Developing Forcefield Parameters for Peptoid Oligomers to Analyze Secondary Structure Formation

Peptoids 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 make 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. Based on the sidechain type and sequence, residue specific interactions can promote or inhibit formation of secondary structures. Furthermore, unlike peptides, which have trans configuration as the prevalent amide bond isomer, peptoid amide bonds can have both cis- and trans- configurations. This allows peptoids to exhibit a variety of secondary structures that are not observed in peptides.

Due to these differences and the varied secondary structures accessible by peptoids, 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. In this work, we present an extension of our approach to model peptoids where we focus on increasing the applicability of the developed NTOID model to peptoid oligomers.

Recently, an online utility known as the Peptoid Data Bank [2] has been developed, which stores experimental structural and XRD crystallographic data for peptoids. Using an application of the utility, we were able to determine the next sidechain residues to consider, based on the number of papers published focusing on each of them. This pointed us to two residues, (S)-N-(1-tertiary butyl ethyl) glycine and (S)-N-(1-naphthylethyl) glycine. The parameters for these sidechains were optimized using Well Tempered Metadynamics in the software package GROMACS while fitting to the structural preferences observed in solution. Using Parallel Bias Metadynamics (PBMetaD) with the developed parameters, we study the formation of É‘-helices by pentamer peptoid oligomers formed using these sidechains. PBMetaD allowed us to analyze all possible conformations of the pentamers and obtain the most stable configurations. These parameters, coupled with the 3 already fitted sidechains to the forcefield, allows 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)