Multiscale collaboration leads to monumental multiscale modeling

ByKatie Mitzelfelt

How individuals, labs, centers, and institutions collaborated to produce the first ever computational model showing changes at the protein level manifesting at the protein, sarcomere, cell, tissue, and organ level.

Logos and images of institutions, centers, and labs collaborating.

A new study made partially possible by the CTMR Quantitative Analysis Core Resources was recently published in the Proceedings of the National Academy of Sciences (PNAS). This work is the result of a decade-long, multi-institutional collaboration and cooperative research efforts between Dr. Mike Regnier at UW and Dr. Andrew McCulloch, at UCSD.

These collaborations began in 2015, with the NIH-funded National Biomedical Computational Resource (NBCR) for which Dr. McCulloch and colleague, Dr. Andrew McCammon were the principal investigators. The Center had supplemental funding to computationally examine significant biological problems and coincidentally, Dr. Regnier’s group had significant biological problem:
Understanding mechanistically how replacing just 2% of the adenosine triphosphate (ATP) pool in cardiac muscle cells with 2’-deoxy-ATP (dATP), a myosin activator, improves cardiac function at the organ level.

The collaborative efforts over the last decade unveiled an understanding of the therapeutic mechanisms of dATP in the failing heart. These include dATP’s ability to 1) increase the pool of myosin heads that are available for engaging in the crossbridge cycle at the molecular level and 2) increase calcium handling in the myocytes by speeding up the pump (SERCA) that returns calcium to its storage location at the cellular level. Together these small-scale changes improve contractile function at the tissue level and pumping efficiency of the heart at the organ level and can improve cardiac function in models of heart failure.

Image of 2 people viewing a computer screen with logos for the CTMR and HAMM Lab
Dr. Matt Childers (left) and Dr. Mike Regnier (right), both of the Heart and Muscle Mechanics (HAMM) Lab and CTMR at UW, viewing a showing a Molecular Dynamics (MD) simulation of the muscle contractile protein myosin.

During the collaboration, the CTMR, directed by Dr. Regnier, came into being in 2019. The CTMR computational resources were able to take over for the NBCR, which ended in 2020. Together the Centers have trained multiple trainees, who have gone onto successful careers in biomedical research.

First author of the PNAS study, Dr. Abby Teitgen, and second author, Dr. Marcus Hock, both recently receiving PhDs from UCSD in Dr. McCulloch’s lab.  They visited the UW-CTMR and received additional training from the Quantitative Analysis Core’s Dr. Matt Childers. The combined expertise and resources at the individual, lab, and center levels, made possible this first ever multi-scale computational model that can explain how the effects of a small molecule therapeutic (dATP) or genetic mutations cause local angstrom-scale changes in protein structure and how this manifests up through cells, tissue, and the whole heart to predict the effects on function. 

3 people at a computer
Dr. Marcus Hock (left) and Dr. Abby Teitgen (middle), both recent graduates of the Cardiac Mechanics Research Group, led by Dr. Andrew McCulloch (top, right), head of the National Biomedical Computation Resource (NBCR) prior to its end.

Congratulations to the team!

For more information, please check out the article from the UW Institute for Stem Cell & Regenerative Medicine’s (ISCRM) website.

Read the full scientific article in PNAS here.