A Modular and Extensible CHARMM-Compatible Model for All-Atom Simulation of Polypeptoids

TL;DR

This paper introduces a modular, extensible CHARMM-compatible model for all-atom simulation of peptoids, enabling efficient incorporation of diverse side chains without reparameterization, validated against experimental and ab initio data.

Contribution

The authors develop a modular extension of the CGenFF-NTOID force field that allows direct addition of arbitrary side chains, simplifying parameterization for peptoid simulations.

Findings

Validated against ab initio calculations and experimental data.

Includes all 20 natural amino acid side chains and 13 synthetic ones.

Provides an open-source tool for automated structure generation.

Abstract

Peptoids (N-substituted glycines) are a class of sequence-defined synthetic peptidomimetic polymers with applications including drug delivery, catalysis, and biomimicry. Classical molecular simulations have been used to predict and understand the conformational dynamics of single peptoid chains and their self-assembly into diverse morphologies including sheets, tubes, spheres, and fibrils. The CGenFF-NTOID model based on the CHARMM General ForceField has demonstrated success in enabling accurate all-atom molecular modeling of the structure and thermodynamic behavior of peptoids. Extension of this force field to new peptoid side chain chemistries has historically required parameterization of new side chain bonded interactions against ab initio and/or experimental data. This fitting protocol improves the accuracy of the force field but is also burdensome and time consuming, and precludes modular extensibility of the model to arbitrary peptoid sequences. In this work, we develop and demonstrate a Modular Side Chain CGenFF-NTOID (MoSiC-CGenFF-NTOID) as an extension of CGenFF-NTOID employing a modular decomposition of the peptoid backbone and side chain parameterizations wherein arbitrary side chain chemistries within the large family of substituted methyl groups (i.e., -CH3, -CH2R, -CHRR' -CRR'R'') are directly ported from CGenFF without any additional reparameterization. We validate this approach against ab initio calculations and experimental data to to develop a MoSiC-CGenFF-NTOID model for all 20 natural amino acid side chains along with 13 commonly-used synthetic side chains, and present an extensible paradigm to efficiently determine whether a novel side chain can be directly incorporated into the model or whether refitting of the CGenFF parameters is warranted. We make the model freely available to the community along with a tool to perform automated initial structure generation.