Bottom-up simulation, reconstruction, and quantification of macromolecule sequences from experimental polymerizations

07 May 2025, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Motivated by the canonical sequence-structure-function paradigm, tools to characterize chemical patterning in natural biomacromolecules, from proteins to nucleic acids, have grown exponentially in recent years. However, analogous strategies for synthetic macromolecules remain in nascent stages, complicated by sequence polydispersity and analytical limitations. To address this, we have developed a comprehensive and open-source Python software, PRISM (polymer rate insights and sequence modeling), that provides quantitative and qualitative metrics for describing chemical patterning in stochastic polymers. First, a numerical integration strategy was constructed to simulate and fit experimental data from reversible addition-fragmentation chain transfer (RAFT) polymerization kinetics, enabling facile estimation of relevant reactivity ratios. These ratios were then used in a mechanism-specific stochastic kinetic simulation strategy to simulate sequence ensembles corresponding to model systems spanning experimental copolymers, classes of statistical polymers (e.g., alternating, block, gradient), and multiblock copolymers. Finally, inspired by sequence homology metrics from bioinformatics, we introduce visualization strategies and quantitative metrics to facilitate comparisons of different sequence ensembles. As the sequence-structure-function paradigm becomes increasingly central in de novo design of synthetic macromolecules, this toolkit provides a first step towards accurate and representative sequence description and featurization.

Keywords

polymerization kinetics
sequence reconstruction
polymer representation

Supplementary materials

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Supporting Information
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Supporting information contains theory and algorithms, general information, and experimental methods as well as supplemental figures and tables including NMR, SEC chromatograms
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