Predicting the effects of dATP on cardiac contraction using multiscale modeling of the sarcomere

McCabe, Kimberly J.; Aboelkassem, Yasser; Teitgen, Abigail E.; Huber, Gary L.; McCammon, J. Andrew; Regnier, Michael; McCulloch, Andrew D.

doi:10.1016/j.abb.2020.108582

Cited by 7 publications

(5 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cellular relaxation kinetics are also improved, perhaps due to improved calcium decay kinetics (Fig. 1m) and the maintenance of the myosin in its activated state during relaxation, which may further facilitate subsequent contractions 22,49 . Thus, in contrast to myotropes like Omecamtiv mecarbil (OM) 8,9 , dATP increases myosin cycling and sarcomere function without prolonging the systole (Fig.1, Table S2) 47,50 or shortening diastole, which makes it a energy-efficient myotrope.…”

Section: Discussionmentioning

confidence: 99%

dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function

Mhatre

Murray

Flint

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ~1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.

show abstract

Section: Discussionmentioning

confidence: 99%

dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function

Mhatre

Murray

Flint

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…86,87 McCulloch, Regnier, and colleagues have employed BD simulations to study actin-protein interactions and develop multiscale models of cardiac myofilament activation and sarcomere contraction. [88][89][90] dATP is known to increase contractile force in hearts. Powers et al 88 investigated the mechanism and found that the deoxy hydrolysis product, 2-deoxy-adenosine 5 0 -diphosphate (dADP), restructures the prepowerstroke myosin.…”

Section: Microtubule Elongation and Myofilament Dynamicsmentioning

confidence: 99%

“…McCulloch, Regnier, and colleagues have employed BD simulations to study actin‐protein interactions and develop multiscale models of cardiac myofilament activation and sarcomere contraction 88–90 . dATP is known to increase contractile force in hearts.…”

Section: Applicationsmentioning

confidence: 99%

“…This was explained by an allosteric effect of dADP binding, resulting in enhanced electrostatic steering due to a conformational change of myosin. Subsequently, these rates were incorporated into a Markov Chain Monte Carlo model of cooperative sarcomere contraction, 89 providing details about the mechanism and effects of dATP on the actin/myosin powerstroke compared to the native ATP.…”

Section: Applicationsmentioning

confidence: 99%

See 1 more Smart Citation

Brownian dynamics simulations of biomolecular diffusional association processes

Muñiz‐Chicharro

Votapka

Amaro

et al. 2022

WIREs Comput Mol Sci

View full text Add to dashboard Cite

Brownian dynamics (BD) is a computational method to simulate molecular diffusion processes. Although the BD method has been developed over several decades and is well established, new methodological developments are improving its accuracy, widening its scope, and increasing its application. In biological applications, BD is used to investigate the diffusive behavior of molecules subject to forces due to intermolecular interactions or interactions with material surfaces. BD can be used to compute rate constants for diffusional association, generate structures of encounter complexes for molecular binding partners, and examine the transport properties of geometrically complex molecules. Often, a series of simulations is performed, for example, for different protein mutants or environmental conditions, so that the effects of the changes on diffusional properties can be estimated. While biomolecules are commonly described at atomic resolution and internal molecular motions are typically neglected, coarse‐graining and the treatment of conformational flexibility are increasingly employed. Software packages for BD simulations of biomolecules are growing in capabilities, with several new packages providing novel features that expand the range of questions that can be addressed. These advances, when used in concert with experiment or other simulation methods, such as molecular dynamics, open new opportunities for application to biochemical and biological systems. Here, we review some of the latest developments in the theory, methods, software, and applications of BD simulations to study biomolecular diffusional association processes and provide a perspective on their future use and application to outstanding challenges in biology, bioengineering, and biomedicine. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Software > Simulation Methods

show abstract

“…The altered myosin motor structure caused by mutations associated with cardiac dysfunction raises the question of whether myosin structure can be targeted for therapeutic intervention. Some myosin-targeted small molecules [e.g., Omecamtiv Mecarbil (201) and 2-deoxy-ATP (115,143)] have been shown to alter myosin structure, providing beneficial functional effects.…”

Section: Structure-function Relationships Of Myosin From Pathological...mentioning

confidence: 99%

The Sliding Filament Theory Since Andrew Huxley: Multiscale and Multidisciplinary Muscle Research

Powers

Malingen

Regnier

et al. 2021

Annu. Rev. Biophys.

Self Cite

View full text Add to dashboard Cite

Two groundbreaking papers published in 1954 laid out the theory of the mechanism of muscle contraction based on force-generating interactions between myofilaments in the sarcomere that cause filaments to slide past one another during muscle contraction. The succeeding decades of research in muscle physiology have revealed a unifying interest: to understand the multiscale processes—from atom to organ—that govern muscle function. Such an understanding would have profound consequences for a vast array of applications, from developing new biomimetic technologies to treating heart disease. However, connecting structural and functional properties that are relevant at one spatiotemporal scale to those that are relevant at other scales remains a great challenge. Through a lens of multiscale dynamics, we review in this article current and historical research in muscle physiology sparked by the sliding filament theory. Expected final online publication date for the Annual Review of Biophysics, Volume 50 is May 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

show abstract

Predicting the effects of dATP on cardiac contraction using multiscale modeling of the sarcomere

Cited by 7 publications

References 32 publications

dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function

dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function

Brownian dynamics simulations of biomolecular diffusional association processes

The Sliding Filament Theory Since Andrew Huxley: Multiscale and Multidisciplinary Muscle Research

Contact Info

Product

Resources

About