# Theory and Modeling of Biomolecules and their Interactions

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $831,554

## Abstract

Project Summary/Abstract
The establishment of tools and methods from statistical mechanics and computer simulation technology to
enable the exploration of biological molecules and their interactions plays a central role in discovery within
biomedical research. This proposal represents a request for support of our ongoing efforts in this area and
includes objectives to address challenges in the theory and modeling associated with these problems, as well
as strategically chosen collaborations that will help elucidate important biomedical questions and provide crucial
tests of the approaches we develop. Our proposed development efforts include the exploration of receptor-ligand
interactions and the thermodynamics of ligand binding to biological receptors through the continued development
and application of novel methods of free energy simulations to ligand binding thermodynamics, docking and
receptor-ligand interaction modeling. The continued refinement, hardening and application of theoretical and
computational methods of constant pH molecular dynamics to integrate the critical aspects of pH and protonation
state changes in protein and nucleic acid receptors and their ligands in molecular simulations and modeling
represents another challenge we will continue to address with the proposed work. Finally, software
infrastructure, specifically the CHARMM macromolecular simulation package, provides the framework for
advancing our methodological approaches and enabling the broader community to explore biomedically
motivated questions via its wide usage and distribution. A component of our proposed efforts will be to continue
the innovative implementation of methods and simulation approaches into this community standard software
package. We will balance and drive our development efforts in the areas of free energy simulations, ligand –
receptor docking and pH-mediated structure-function processes, important to a deeper mechanistic
understanding of biomedically directed questions, through strategic collaborations with experimental colleagues
in the areas of: transcriptional activation based on small amphipathic molecules targeting co-activators from the
CREB binding protein (KIX) and the AciD domain of Med25; key cancer targets such as menin-MLL protein-
protein interaction inhibition; inhibitors of acyl protein thioesterases, targeted in anti-cancer therapies for
oncogenic HRas; enzyme redesign and substrate scope expansion to better understand the evolution of function
of a novel Flavin-dependent hydroxylase in exploiting complex chemical transformations important in the
development of pharmaceuticals; pH-regulated sensors in kinase signaling associated with the G-protein from
the tetrameric Gai protein; the pH-modulated switch for myristoylated histactophilin, the actin binding protein that
is structurally homologous with interleukin-1b and fibroblast growth factor. Finally, we will engage experts in the
development of big data applications of molecular ...

## Key facts

- **NIH application ID:** 9858372
- **Project number:** 5R35GM130587-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** CHARLES L BROOKS
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $831,554
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858372

## Citation

> US National Institutes of Health, RePORTER application 9858372, Theory and Modeling of Biomolecules and their Interactions (5R35GM130587-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9858372. Licensed CC0.

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