# Multiscale Modeling of Enzymatic Reactions and Firefly Bioluminescence

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA · 2022 · $254,459

## Abstract

Abstract
Enzyme functionality is a critical component of all life systems. Whereas advances in
experimental methodology have enabled a better understanding of factors that control
enzyme function, critical components of the reaction space such as highly unstable
intermediates and transition states are best accessed for evaluation through
computational simulations. Similarly, computational methodology continues to provide a
key resource for probing excited-state processes such as bioluminescence.
Combined ab initio quantum mechanical molecular mechanical (ai-QM/MM) simulations
are, in principle, the preferred choice in the modeling of both processes. But ai-QM/MM
modeling of enzymatic reactions is now severely limited by its computational cost, where
a direct ai-QM/MM free energy simulation of an enzymatic reaction can take 500,000 or
more CPU hours. Meanwhile, ai-QM/MM modeling of firefly bioluminescence is also
hindered by the computational accuracy, where it has yet to produce quantitatively
correct predictions for the bioluminescence spectral shift with site-directed mutagenesis.
The goal of this proposal is to accelerate ai-QM/MM simulations of enzymatic reaction
free energy and to improve the quality of ai-QM/MM-simulated bioluminescence spectra,
so that ai-QM/MM simulations can be routinely performed by experimental groups. This
will be achieved via a) using a lower-level (semi-empirical QM/MM) Hamiltonian for
sampling; b) an enhancement to the similarity between the two Hamiltonians by
calibrating the low-level Hamiltonian using the reaction pathway force matching
approach, in conjunction with several other methods.
The expected outcomes of this collaborative effort include: a) advanced methodologies
for accelerated reaction free energy simulations and accurate bioluminescence spectra
predictions, which will be released through multiple software platforms; b) a fundamental
understanding of reactions such as Kemp elimination and polymerase-eta catalyzed
DNA replication; c) a deeper insight into the role of macromolecular environment in the
modulation of enzyme catalytic activities or bioluminescence wavelengths, which can
further enhance our capability of designing new enzymes and bioluminescence probes.

## Key facts

- **NIH application ID:** 10476326
- **Project number:** 5R01GM135392-04
- **Recipient organization:** UNIVERSITY OF OKLAHOMA
- **Principal Investigator:** Yihan Shao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $254,459
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476326

## Citation

> US National Institutes of Health, RePORTER application 10476326, Multiscale Modeling of Enzymatic Reactions and Firefly Bioluminescence (5R01GM135392-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10476326. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*