@article {43400,
	title = {Multiscale computational modeling of the effects of 2{\textquoteright}-deoxy-ATP on cardiac muscle calcium handling},
	journal = {Journal of Applied Physics},
	volume = {134},
	year = {2023},
	month = {08/2023},
	publisher = {AIP Publishing},
	abstract = {2{\textquoteright}-Deoxy-ATP (dATP), a naturally occurring near analog of ATP, is a well-documented myosin activator that has been shown to increase contractile force, improve pump function, and enhance lusitropy in the heart. Calcium transients in cardiomyocytes with elevated levels of dATP show faster calcium decay compared with cardiomyocytes with basal levels of dATP, but the mechanisms behind this are unknown. Here, we design and utilize a multiscale computational modeling framework to test the hypothesis that dATP acts on the sarcoendoplasmic reticulum calcium-ATPase (SERCA) pump to accelerate calcium re-uptake into the sarcoplasmic reticulum during cardiac relaxation. Gaussian accelerated molecular dynamics simulations of human cardiac SERCA2A in the E1\&nbsp;apo, ATP-bound and dATP-bound states showed that dATP forms more stable contacts in the nucleotide binding pocket of SERCA and leads to increased closure of cytosolic domains. These structural changes ultimately lead to changes in calcium binding, which we assessed using Brownian dynamics simulations. We found that dATP increases calcium association rate constants to SERCA and that dATP binds to\&nbsp;apo\&nbsp;SERCA more rapidly than ATP. Using a compartmental ordinary differential equation model of human cardiomyocyte excitation-contraction coupling, we found that these increased association rate constants contributed to the accelerated rates of calcium transient decay observed experimentally. This study provides clear mechanistic evidence of enhancements in cardiac SERCA2A pump function due to interactions with dATP.},
	doi = {https://doi.org/10.1063/5.0157935},
	author = {Marcus T. {Hock} and Teitgen, Abigail and Kimberly J {McCabe} and Sophia P. {Hirakis} and Huber, Gary and Regnier, Michael and Rommie E. {Amaro} and Andrew J. {McCammon} and Andrew D. {McCulloch}}
}
@article {26563,
	title = {Cardiac myosin activation with 2-deoxy-ATP via increased electrostatic interactions with actin},
	journal = {Proceedings of the National Academy of Sciences},
	year = {2019},
	month = {05/2019},
	publisher = {PNAS},
	abstract = {The naturally occurring nucleotide 2-deoxy-adenosine 5'-triphosphate (dATP) can be used by cardiac muscle as an alternative energy substrate for myosin chemomechanical activity. We and others have previously shown that dATP increases contractile force in normal hearts and models of depressed systolic function, but the structural basis of these effects has remained unresolved. In this work, we combine multiple techniques to provide structural and functional information at the angstrom-nanometer and millisecond time scales, demonstrating the ability to make both structural measurements and quantitative kinetic estimates of weak actin{\textendash}myosin interactions that underpin sarcomere dynamics. Exploiting dATP as a molecular probe, we assess how small changes in myosin structure translate to electrostatic-based changes in sarcomere function to augment contractility in cardiac muscle. Through Brownian dynamics simulation and computational structural analysis, we found that deoxy-hydrolysis products [2-deoxy-adenosine 5'-diphosphate (dADP) and inorganic phosphate (Pi)] bound to prepowerstroke myosin induce an allosteric restructuring of the actin-binding surface on myosin to increase the rate of cross-bridge formation. We then show experimentally that this predicted effect translates into increased electrostatic interactions between actin and cardiac myosin in vitro. Finally, using small-angle X-ray diffraction analysis of sarcomere structure, we demonstrate that the proposed increased electrostatic affinity of myosin for actin causes a disruption of the resting conformation of myosin motors, resulting in their repositioning toward the thin filament before activation. The dATP-mediated structural alterations in myosin reported here may provide insight into an improved criterion for the design or selection of small molecules to be developed as therapeutic agents to treat systolic dysfunction.},
	issn = {0027-8424},
	doi = {10.1073/pnas.1905028116},
	url = {http://www.pnas.org/lookup/doi/10.1073/pnas.1905028116https://syndication.highwire.org/content/doi/10.1073/pnas.1905028116},
	author = {Joseph D {Powers} and Yuan, Chen-Ching and Kimberly J {McCabe} and Jason D {Murray} and Matthew Carter {Childers} and Galina V {Flint} and Moussavi-Harami, Farid and Mohran, Saffie and Castillo, Romi and Zuzek, Carla and Ma, Weikang and Daggett, Valerie and Andrew D. {McCulloch} and Thomas C {Irving} and Regnier, Michael}
}
