# Multiscale Modeling of Enzymatic Reactions and Bioimaging Probes

> **NIH NIH R35** · UNIVERSITY OF OKLAHOMA · 2024 · $394,119

## Abstract

Multiscale Modeling of Enzymatic Reactions and Bioimaging Probes
Abstract
 This project addresses a critical technology/software gap — the accessibility of ab initio quantum mechan-
ical molecular mechanical (QM/MM) multiscale modeling tools in the enzymology and bioimaging fields — by
developing machine-learning-based and physics-based electronic structure and molecular simulation methods.
In our R01 funding period, we made several methodological advances, especially (a) the first !-learning poten-
tial for simulating the enzyme reaction free energy (as demonstrated with the modeling of chorismate mutase
catalysis), (b) an advance to the multiple time-step free energy simulation methodology, and (c) an analysis tool
for interpreting/predicting the substitution effect on chromophore emission wavelength based on chromophore-
substituent orbital interactions.
 Building on these method developments, we will further develop robust active-learning protocols for training
!-learning potentials for ground and excited electronic states for systems in the macromolecular or solvent en-
vironments. These !-learning potentials, when validated against advanced physics-based models, will enable
routine (a) enzyme reaction simulations and (b) optoacoustic and other bioimaging probe modeling in our lab and
the larger community.
 CRISPR-Cas proteins will be used as our primary test enzyme systems. We will employ the !-learning
potentials in molecular dynamics simulations and seek an atomistic understanding of (a) the effect of SpyCas9
conformational changes on HNH- and RuvC-domain catalyzed DNA cleavage activity, and (b) the mechanism of
AsCas12a and FnCas12a RuvC-domain catalyzed non-target strand DNA cleavage.
 For bioimaging probes, we will seek general guiding principles for designing optoacoustic imaging probes.
It will be achieved by performing ab initio-QM/MM-quality multiscale modeling to explore the impact of struc-
tural modifications (especially the attachment of halogen atoms and flexible alkane chains) on the molecular
absorbance and nonradiative decay rate, both key factors in the optoacoustic signal generation.

## Key facts

- **NIH application ID:** 10841944
- **Project number:** 1R35GM153297-01
- **Recipient organization:** UNIVERSITY OF OKLAHOMA
- **Principal Investigator:** Yihan Shao
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $394,119
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841944

## Citation

> US National Institutes of Health, RePORTER application 10841944, Multiscale Modeling of Enzymatic Reactions and Bioimaging Probes (1R35GM153297-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841944. Licensed CC0.

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