# A multiscale computational and experimental platform to investigate cardiomyopathies and targeted therapeutics

> **NIH NIH K99** · UNIVERSITY OF WASHINGTON · 2024 · $135,840

## Abstract

PROJECT SUMMARY
In deadly and common familial hypertrophic and dilated cardiomyopathies, structural variation at the single
protein level leads to adverse ventricular remodeling, systolic dysfunction, and diastolic dysfunction. Muscle
contraction is driven by interactions among motor proteins, structural filaments, and regulatory proteins within
sarcomeres. Structural perturbations to the contractile machinery disrupt the kinetics of these interactions and
give rise to systems-level dysfunction in cardiac tissue. This project will investigate the mechanisms of cardiac
contractile dysfunction across multiple biologically relevant spatial and temporal scales using a combined
computational and experimental platform. The proposed work focuses specifically on structural perturbations
that impact the essential interaction between actin and myosin. The overarching hypothesis of this work is that
structural perturbations along a structural communication pathway within the upper and lower 50 kDa domains
of myosin modulate the electrostatic potential and surface area of myosin’s actin binding surface and modulate
the association of myosin heads onto thin filaments. Recent stopped flow kinetics and x-ray diffraction-based
measurements have shown that cardiomyopathy mutations and the small molecule 2’-deoxy-ATP modulate
actomyosin affinity. I have used computational simulations to show that these mutations and small molecules
alter the structure and dynamics of the upper 50 kDa domain of myosin. However, a general description of the
‘rules’ by which mutations and/or small molecules modulate actomyosin interaction requires further study. These
computational predictions also require rigorous testing using in vitro methods. The goals of this work are to
establish a mechanistic framework that explains how structural perturbations to myosin affect its interaction with
actin and to modify actin-myosin interactions with small molecules designed to modulate myosin structure. These
goals will be accomplished by simulating the impact of mutations on myosin structure, myosin
recruitment, and actomyosin interaction (Aim 1), testing computational predictions in single molecules
and contractile organelles from stem cell-derived cardiomyocytes (Aim 2), and developing small
molecules designed to modulate actin-myosin interactions by targeting structural communication
pathways in myosin (Aim 3). The project will utilize machine-learning infused computational workflows and
state-of-the-art stem cell technologies to accelerate translational cardiomyopathy research with a combined
computational/experimental platform. The proposed training program will provide me with new skills in stem cell
biology, protein biochemistry, and muscle mechanics that increase the scope of my research. I will be mentored
by a diverse team led by Dr. Michael Regnier, an accomplished researcher in muscle biology who has significant
experience in leading collaborative, multiscale, and interdisciplinary...

## Key facts

- **NIH application ID:** 10864724
- **Project number:** 1K99HL173646-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Matthew Carter Childers
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $135,840
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10864724

## Citation

> US National Institutes of Health, RePORTER application 10864724, A multiscale computational and experimental platform to investigate cardiomyopathies and targeted therapeutics (1K99HL173646-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10864724. Licensed CC0.

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