UCSD - University of California - San Diego
08/19/2024 | Press release | Distributed by Public on 08/19/2024 15:08
Simulations from Atom to Organ Reveal Novel Treatment Mechanisms for Heart Failure
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August 19, 2024Article Content
A team of researchers from the University of California San Diego has developed the first multiscale computational model to simulate the therapeutic mechanisms of a drug candidate for heart failure from the atomic level to the organ system scale. The analysis, published on Aug. 19 in the Proceedings of the National Academy of Sciences (PNAS), spans atomistic models of a small molecule and its interactions with the molecular motors of the heart, up to cellular predictions of cardiac muscle contraction and even a whole heart simulation of cardiac pumping and the effects on cardiovascular system performance.
The study provides new insights into the mechanisms by which a naturally occurring small molecule - deoxy-ATP (dATP )- can improve cardiac pumping in heart failure. The multiscale models suggest that converting just 7% of the molecule adenosine triphosphate (ATP) in cardiac muscle to dATP could completely reverse the loss of cardiac pumping function in heart failure without impairing energy efficiency or other important cardiac functions. The beneficial therapeutic effects of dATP take place at multiple scales and were much greater in the failing heart than in the normal heart, which was unaffected by the drug.
First author Abby Teitgen (right) and second author Marcus Hock (left) are recent Ph.D. graduates from UC San Diego's Shu Chien-Gene Lay Department of Bioengineering. The computer screen shows the crystal structure of the myosin protein and the predicted therapeutic benefits of deoxy-ATP on the failing heart.
The research was led by Andrew McCulloch, a distinguished professor in the Shu Chien - Gene Lay Department of Bioengineering at UC San Diego and director of the Institute of Engineering in Medicine. First author Abby Teitgen and second author Marcus Hock both recently earned PhDs in bioengineering in McCulloch's lab. The research was conducted in collaboration with Kimberly McCabe, another PhD graduate of the McCulloch lab now at Simula Research Institute, along with J. Andrew McCammon, distinguished research professor of Chemistry and Biochemistry at UC San Diego and Gary Huber, a project scientist in Chemistry and Biochemistry. These collaborators developed one of the key molecular simulation tools that made it possible to bridge molecular simulations at atomic resolution to the scale of interactions between the cardiac muscle contractile proteins.
Collaborating investigators at the University of Washington, Professor Michael Regnierand postdoctoral scholar Matthew Childers, have been systematically testing dATP as a possible new therapy for heart failure using experiments at all scales of biological organization from molecule to organism. In the past, they used molecular simulations to uncover how replacing even just 1% of the ATP in cardiac muscle cells with dATP can enhance the contractile function of myosin, the cardiac muscle molecular motor. How these molecular mechanisms translate in the scale of the whole cardiovascular system- where the symptoms of heart failure manifest themselves in the clinic- remained unknown. To tackle this, the research team collaborated with Professor Daniel Beardand former postdoctoral scholar Bahador Marzbanin the Physiology department at the University of Michigan. Their models were used to simulate cardiac energy metabolism and cardiovascular dynamics at the scale of the heart and cardiovascular system.
This first-of-its-kind research opens up exciting new possibilities in the development of new molecular therapeutics for heart disease. By bridging the atomic scale- where small molecular drugs interact with their biological target- to influence organ system physiology and the clinical signs and symptoms of disease, this breakthrough in multiscale modeling promises a new era of improved and accelerated drug discovery.
Paper: "Multiscale modeling shows how 2'-deoxy-ATP rescues ventricular function in heart failure"
This work was supported by the National Institutes of Health, the Wu Tsai Human Performance Alliance and the Joe and Clara Tsai Foundation.
Competing interest statement: McCulloch is a co-founder of and has equity interests in Insilicomed Inc. and Vektor Medical, Inc. He serves as a scientific advisor to both companies. Some of McCulloch's research grants have been identified for conflict of interest management based on the overall scope of the project and its potential benefit to Insilicomed Inc. and Vektor Medical, Inc. The author is required to disclose this relationship in publications acknowledging the grant support; however, the research subject and findings reported in this study did not involve the companies in any way and have no relationship with the business activities or scientific interests of either company. The terms of this arrangement have been reviewed and approved by the University of California.