Molecular Origins of Catalysis in Random Heteropolymer Enzyme Mimics through All-Atom Simulations
9 affiliations
- 1Department of Materials Science and Engineering, MIT, Cambridge, Massachusetts 02139, United States
- 2Material Measurement Laboratory, National Institute of Standards and Technology, Gaithersburg, Maryland 20899, United States
- 3Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
- 4Department of Chemical Engineering, MIT, Cambridge, Massachusetts 02139, United States
- 5Division of Chemistry and Chemical Engineering, Caltech, Pasadena, California 91125, United States
- 6Department of Materials Science and Engineering, University of California, Berkeley, Berkeley, California 94704, United States
- 7Department of Chemistry, University of California, Berkeley, Berkeley, California 94704, United States
- 8Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94704, United States
- 9Kavli Energy NanoScience Institute, University of California, Berkeley, Berkeley, California 94704, United States
Abstract
Random heteropolymers (RHPs) have recently emerged as synthetic macromolecules capable of enzyme-inspired catalysis despite lacking defined secondary and tertiary structures. However, the molecular origins of their catalytic activity remain less understood. Here, we use all-atom molecular dynamics simulations to investigate a methacrylate-based RHP shown to experimentally catalyze the selective cyclization of citronellal. Despite its high anionic monomer content, the polymer self-assembles into molten globules with heterogeneous surfaces due to high hydrophobic content. This dynamic organization creates chemically distinct binding interfaces where substrates encounter local environments enriched in specific monomers. Anionic sulfopropyl methacrylate groups preferentially associate with protonated intermediates, providing electrostatic stabilization relevant to catalysis. Free energy calculations reveal a reduced barrier for substrate conformational closure that promotes reactive geometries in hydrophobic environments, relating to hydrophobic patches found on the RHP. We further observe selective adsorption behavior when multiple substrates are present, with isopulegol desorbing more rapidly than citronellal or menthoglycol, consistent with favorable product release and catalytic turnover. Together, these findings demonstrate that RHPs without rigid folds can create dynamic, chemically heterogeneous microenvironments shaped by monomer composition and sequence, enabling electrostatic and geometric stabilization, providing a molecular rationale for their experimentally observed catalytic function.
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BibTeX
@article{hilburg2026molecular,
title = {{Molecular Origins of Catalysis in Random Heteropolymer Enzyme Mimics through All-Atom Simulations}},
author = {Shayna L. Hilburg and Zexiang Han and Tianyi Jin and Priya Ganesh and Hao Yu and Philjun Kang and Ting Xu and Alfredo Alexander-Katz},
journal = {The Journal of Physical Chemistry. B},
year = {2026},
month = oct,
doi = {10.1021/acs.jpcb.6c05638},
url = {https://doi.org/10.1021/acs.jpcb.6c05638},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Molecular Origins of Catalysis in Random Heteropolymer Enzyme Mimics through All-Atom Simulations
AU - Shayna L. Hilburg
AU - Zexiang Han
AU - Tianyi Jin
AU - Priya Ganesh
AU - Hao Yu
AU - Philjun Kang
AU - Ting Xu
AU - Alfredo Alexander-Katz
PY - 2026
DA - 2026/10/18
JO - The Journal of Physical Chemistry. B
DO - 10.1021/acs.jpcb.6c05638
UR - https://doi.org/10.1021/acs.jpcb.6c05638
AB - Random heteropolymers (RHPs) have recently emerged as synthetic macromolecules capable of enzyme-inspired catalysis despite lacking defined secondary and tertiary structures. However, the molecular origins of their catalytic activity remain less understood. Here, we use all-atom molecular dynamics simulations to investigate a methacrylate-based RHP shown to experimentally catalyze the selective cyclization of citronellal. Despite its high anionic monomer content, the polymer self-assembles into molten globules with heterogeneous surfaces due to high hydrophobic content. This dynamic organization creates chemically distinct binding interfaces where substrates encounter local environments enriched in specific monomers. Anionic sulfopropyl methacrylate groups preferentially associate with protonated intermediates, providing electrostatic stabilization relevant to catalysis. Free energy calculations reveal a reduced barrier for substrate conformational closure that promotes reactive geometries in hydrophobic environments, relating to hydrophobic patches found on the RHP. We further observe selective adsorption behavior when multiple substrates are present, with isopulegol desorbing more rapidly than citronellal or menthoglycol, consistent with favorable product release and catalytic turnover. Together, these findings demonstrate that RHPs without rigid folds can create dynamic, chemically heterogeneous microenvironments shaped by monomer composition and sequence, enabling electrostatic and geometric stabilization, providing a molecular rationale for their experimentally observed catalytic function.
SN - 1520-6106
SN - 1520-5207
ER -