A modular and extensible CHARMM-compatible model for all-atom simulation of polypeptoids

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 chains and their self-assembly into morphologies including sheets, tubes, spheres, and fibrils. The CGenFF-NTOID model based on the CHARMM General Force Field has demonstrated success in accurate all-atom molecular modeling of peptoid structure and thermodynamics. Extension of this force field to new peptoid side chains has historically required reparameterization of side chain bonded interactions against ab initio data. This fitting protocol improves the accuracy of the force field but is also burdensome 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 chains within the large family of substituted methyl groups (i.e., –CH₃, –CH₂R, –CHRR', and –CRR'R") are directly ported from CGenFF. We validate this approach against ab initio calculations and experimental data 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.. Authors: Berlaga, Alex [University of Chicago, IL (United States)] (ORCID:0000000163261695); Torkelson, Kaylyn [University of Washington, Seattle, WA (United States)] (ORCID:0009000861646004); Seal, Aniruddha [University of Chicago, IL (United States)] (ORCID:0000000257105378); Pfaendtner, Jim [North Carolina State University, Raleigh, NC (United States)] (ORCID:0000000167272957); Ferguson, Andrew L. [University of Chicago, IL (United States)] (ORCID:0000000288299726). DOE Contract: SC0019288. Subjects: 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Ab-initio methods; Biomimetics; Biopolymers; Classical molecular dynamic simulations; Conformational dynamics; Free energy landscapes; Molecular simulations; Thermodynamics