# Multiscale Modeling of Protein Kinase Structure, Catalysis and Allostery

> **NIH NIH R01** · UNIVERSITY OF TEXAS ARLINGTON · 2021 · $352,937

## Abstract

Multiscale Modeling of Protein Kinase Structure, Catalysis and Allostery
PROJECT SUMMARY/ABSTRACT
The long-term goal of this research is to advance our understanding of the catalytic and regulatory mechanisms
of complex enzymatic systems and the roles of protein dynamics in enzyme function. Protein kinase (PK), the
focus of this study, is an attractive system for this purpose, because it involves both large-scale conformational
change and enzymatic catalysis. Moreover, because of its pathological significance, understanding PK’s
molecular mechanism is of fundamental importance in kinase research and also may provide new insights into
the development of improved therapies against kinases. Our central hypothesis, based on our recent studies
and enzyme kinetic data, is that the catalytic activity of PK is closely associated with its regulatory function.
Therefore, any change in regulatory activity affects the catalytic activity of the kinase, which occurs through
allosteric modulation of underlying protein dynamics, and together control overall activity of PK. This contrasts
with the conventional view that the inactive-to-active conformational change is the main mechanism for regulating
kinase activity. Our objective in this grant is to examine these two contrasting views on the regulation of kinase
activity by the parallel study of two important kinases, insulin receptor kinase (IRK) and adenylate kinase (AdK),
which play critical roles in cell homeostasis, and elucidate their complete molecular mechanisms. These
objectives will be accomplished through quantitative modeling of their conformational change, ligand binding and
catalysis in key functional states, including the fully active and inactive states. The proposed research involves
development of new multiscale simulation methods combining quantum, molecular and statistical mechanical
methods and their extension to permit rapid and accurate determination of kinase mechanisms. Our specific
AIMs are: (1) the development of effective multiscale simulation methods integrating the ab initio/density
functional theory (AI/DFT) and semiempirical (SE) QM/MM methods with the string simulation methods in
CHARMM, their acceleration through advanced parallelization and accelerator algorithms and reaction-specific
parameterizations, and development of efficient alchemical free energy simulation methods overcoming the
limitations of existing methods; 2) elucidation of the mechanisms of IRK catalysis and conformational change
and the connection between its intrinsic protein motions and catalysis of IRK; and 3) determination of the catalytic
mechanism of AdK and the role of active site residues in controlling the active site and global protein dynamics
and the overall activity of AdK. The completion of the proposed study will deepen the mechanistic understanding
of these kinases and the role of protein dynamics in their catalysis. Experimental verification of computational
results will also be made by characte...

## Key facts

- **NIH application ID:** 10240612
- **Project number:** 5R01GM132481-03
- **Recipient organization:** UNIVERSITY OF TEXAS ARLINGTON
- **Principal Investigator:** Kwangho Nam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,937
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240612

## Citation

> US National Institutes of Health, RePORTER application 10240612, Multiscale Modeling of Protein Kinase Structure, Catalysis and Allostery (5R01GM132481-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240612. Licensed CC0.

---

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