# Understanding Essential Protein Dynamics through the Anharmonic Properties of Thermally Excited Vibrations

> **NIH NIH R01** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2023 · $224,175

## Abstract

The selectivity of orthosteric drugs is often limited by the structural similarity of their binding sites in homologous
proteins, while allosteric binding sites are far less conserved. This allows allosteric drugs to bind a target protein
with higher selectivity, which reduces the potential for side-effects and lowers drug toxicity. However, allosteric
drug discoveries have been limited to serendipitous observations because rational allosteric drug design
strategies face several inherent challenges. These challenges are directly related to current limits in the
predictability of protein conformational fluctuations and collective dynamics that are central to the mechanisms
of allosteric drugs. The objective of this project is the development of computational methods to facilitate the
rational design of allosteric drugs via predictions of protein conformational fluctuations and collective dynamics
from all-atom simulations.
In principle, all-atom molecular dynamics simulations can directly explore protein conformational dynamics but
require sampling on timescales of milliseconds to seconds for systems of pharmacological interest. Even with
state-of-the-art enhanced sampling techniques, the associated computational costs and hardware requirements
(special purpose computers, national supercomputers, large distributed computing networks) limit such
applications to a small number of systems. This project aims to make the computational discovery of allosteric
mechanisms in proteins more efficient and achievable with computer hardware available in most research
laboratories and universities. To this end, the methods developed for this project maximize the information on
inherent protein dynamics that can be extracted from molecular dynamics simulations.
These methods will initially be applied to identify allosteric mechanisms in matrix metallo-proteinases (MMPs),
which represent a family of structurally homologous proteins involved in the degradation of the extracellular
matrix. Several members of the MMP family have been identified as drug targets in the context of chronic
inflammatory disease and cancer metastasis. MMPs feature a highly conserved catalytic center, which results
in a low selectivity of orthosteric small molecule inhibitors for individual MMPs and limits their therapeutic use.
This project aims to identify allosteric mechanisms in MMPs that enable the targeted development of highly
selective allosteric MMP inhibitors as potential drug candidates.
The methods developed for this project are general and not specific to MMPs. They will thus be applicable for
the identification of allosteric mechanisms in other drug target proteins and will be made available as open-
source software.

## Key facts

- **NIH application ID:** 10566333
- **Project number:** 1R01GM148622-01
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** Matthias Heyden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $224,175
- **Award type:** 1
- **Project period:** 2023-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10566333

## Citation

> US National Institutes of Health, RePORTER application 10566333, Understanding Essential Protein Dynamics through the Anharmonic Properties of Thermally Excited Vibrations (1R01GM148622-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10566333. Licensed CC0.

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