Dynamic charge distribution as a key driver of catalytic reactivity in an artificial metalloenzyme.
4 affiliations
- 1Department of Chemical Engineering, Massachusetts Institute of Technology Cambridge MA 02139 USA [email protected].
- 2Department of Biological Engineering, Massachusetts Institute of Technology Cambridge MA 02139 USA.
- 3Department of Chemical Sciences, University of Naples Federico II 80126 Naples Italy.
- 4Department of Chemistry, Massachusetts Institute of Technology Cambridge MA 02139 USA.
Abstract
Miniature artificial metalloenzymes provide a simplified platform to extract design principles for engineering catalysts that outperform natural enzymes. Among them, mimochromes (MCs) emerged as excellent candidates for replicating the activity of peroxidases in a compact scaffold composed of a heme center embedded between two helical peptides. However, design optimizations of MCs have largely focused on structural properties, leaving the impact of the electronic environment less explored. To investigate how the electronic environment influences reactivity, we carry out both classical and ab initio molecular dynamics (MD) simulations of a series of mimochromes, MC6, MC6*, and MC6*a, with known differences in reactivity. To uncover patterns in electronic structure, we train supervised machine learning (ML) models and carry out statistical analysis. The ab initio MD simulations uncover key charge coupling interactions between Arg10' and Glu2' that are not identified in classical dynamics. These residues are determined to be essential in orienting Arg10' in the active site. Furthermore, using our ML classifiers trained to distinguish mimochromes based on partial charge dynamics alone, we identify critical residues such as Arg10', Lys11, Glu2', and Ser6' that distinguish the mimochrome analogues. Disruption of the computationally-identified Glu2'⋯Lys11 salt bridge in a new mimochrome analogue, MC6*a-LysBoc, that we synthesize and characterize, experimentally supports this prediction by resulting in a seven-fold decrease in the total turnover number. Quantum mechanical calculations show that Arg10' stabilizes the transition state for the formation of the reactive oxo from hydrogen peroxide. These results indicate that partial charge distribution dynamics are important in the reactivity series in mimochromes, which could provide a complementary method to augment analysis of static electric fields and long-range correlated motions for the engineering of a broad array of next-generation metalloenzymes.
Related
- Borrowing the fold, building the site: non-catalytic protein scaffolds in the age of computational metalloenzyme design
- Recent Advances in Niobium-Mediated Organic Synthesis: Catalytic Modes, Reactivity, Limitations, and Biomass Valorization
- Renewable-compatible urea electrosynthesis enabled by dynamic asymmetric catalytic domains
- Impact of the spatial distribution of positive charges on the catalytic activity of NiSOD bioinspired complexes
- Adaptive Catalytic Interfaces for Biomass-Derived Model Compounds: Dynamic Active Sites, Microenvironments, and Operando-Guided Design
BibTeX
@article{kastner2026dynamic,
title = {{Dynamic charge distribution as a key driver of catalytic reactivity in an artificial metalloenzyme.}},
author = {David W Kastner and Linda Leone and Clorice R Reinhardt and Husain Adamji and Melissa T Manetsch and Alessandra Esposito and Flavia Nastri and Yuriy Román-Leshkov and Angela Lombardi and Heather J Kulik},
journal = {Chemical science},
year = {2026},
month = sep,
doi = {10.1039/d6sc05720a},
url = {https://europepmc.org/article/MED/42948372},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Dynamic charge distribution as a key driver of catalytic reactivity in an artificial metalloenzyme.
AU - David W Kastner
AU - Linda Leone
AU - Clorice R Reinhardt
AU - Husain Adamji
AU - Melissa T Manetsch
AU - Alessandra Esposito
AU - Flavia Nastri
AU - Yuriy Román-Leshkov
AU - Angela Lombardi
AU - Heather J Kulik
PY - 2026
DA - 2026/09/29
JO - Chemical science
DO - 10.1039/d6sc05720a
UR - https://europepmc.org/article/MED/42948372
AB - Miniature artificial metalloenzymes provide a simplified platform to extract design principles for engineering catalysts that outperform natural enzymes. Among them, mimochromes (MCs) emerged as excellent candidates for replicating the activity of peroxidases in a compact scaffold composed of a heme center embedded between two helical peptides. However, design optimizations of MCs have largely focused on structural properties, leaving the impact of the electronic environment less explored. To investigate how the electronic environment influences reactivity, we carry out both classical and ab initio molecular dynamics (MD) simulations of a series of mimochromes, MC6, MC6*, and MC6*a, with known differences in reactivity. To uncover patterns in electronic structure, we train supervised machine learning (ML) models and carry out statistical analysis. The ab initio MD simulations uncover key charge coupling interactions between Arg10' and Glu2' that are not identified in classical dynamics. These residues are determined to be essential in orienting Arg10' in the active site. Furthermore, using our ML classifiers trained to distinguish mimochromes based on partial charge dynamics alone, we identify critical residues such as Arg10', Lys11, Glu2', and Ser6' that distinguish the mimochrome analogues. Disruption of the computationally-identified Glu2'⋯Lys11 salt bridge in a new mimochrome analogue, MC6*a-LysBoc, that we synthesize and characterize, experimentally supports this prediction by resulting in a seven-fold decrease in the total turnover number. Quantum mechanical calculations show that Arg10' stabilizes the transition state for the formation of the reactive oxo from hydrogen peroxide. These results indicate that partial charge distribution dynamics are important in the reactivity series in mimochromes, which could provide a complementary method to augment analysis of static electric fields and long-range correlated motions for the engineering of a broad array of next-generation metalloenzymes.
SN - 2041-6520
SN - 2041-6539
ER -