@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 {27460,
	title = {Predicting the effects of dATP on cardiac contraction using multiscale modeling of the sarcomere},
	journal = {Archives of Biochemistry and Biophysics},
	volume = {695},
	year = {2020},
	month = {11/2020},
	pages = {108582},
	publisher = {Elsevier},
	abstract = {2{\textquoteright}-deoxy-ATP (dATP) is a naturally occurring small molecule that has shown promise as a therapeutic because it significantly increases cardiac myocyte force development even at low dATP/ATP ratios. To investigate mechanisms by which dATP alters myosin crossbridge dynamics, we used Brownian dynamics simulations to calculate association rates between actin and ADP- or dADP-bound myosin. These rates were then directly incorporated in a mechanistic Monte Carlo Markov Chain model of cooperative sarcomere contraction. A unique combination of increased powerstroke and detachment rates was required to match experimental steady-state and kinetic data for dATP force production in rat cardiac myocytes when the myosin attachment rate in the model was constrained by the results of a Brownian dynamics simulation. Nearest-neighbor cooperativity was seen to contribute to, but not fully explain, the steep relationship between dATP/ATP ratio and steady-state force-development observed at lower dATP concentrations. Dynamic twitch simulations performed using measured calcium transients as inputs showed that the effects of dATP on the crossbridge alone were not sufficient to explain experimentally observed enhancement of relaxation kinetics by dATP treatment. Hence, dATP may also affect calcium handling even at low concentrations. By enabling the effects of dATP on sarcomere mechanics to be predicted, this multi-scale modelling framework may elucidate the molecular mechanisms by which dATP can have therapeutic effects on cardiac contractile dysfunction.},
	doi = {10.1016/j.abb.2020.108582},
	author = {Kimberly J {McCabe} and Aboelkassem, Yasser and Teitgen, Abigail and Huber, Gary and Andrew J. {McCammon} and Regnier, Michael and Andrew D. {McCulloch}}
}
@article {26786,
	title = {A Stochastic Multiscale Model of Cardiac Thin Filament Activation Using Brownian-Langevin Dynamics},
	journal = {Biophysical Journal},
	volume = {117},
	year = {2019},
	pages = {2255-2272},
	publisher = {Cell Press},
	abstract = {We use Brownian-Langevin dynamics principles to derive a coarse-graining multiscale myofilament model that can describe the thin-filament activation process during contraction. The model links atomistic molecular simulations of protein-protein interactions in the thin-filament regulatory unit to sarcomere-level activation dynamics. We first calculate the molecular interaction energy between tropomyosin and actin surface using Brownian dynamics simulations. This energy profile is then generalized to account for the observed tropomyosin transitions between its regulatory stable states. The generalized energy landscape then served as a basis for developing a filament-scale model using Langevin dynamics. This integrated analysis, spanning molecular to thin-filament scales, is capable of tracking the events of the tropomyosin conformational changes as it moves over the actin surface. The tropomyosin coil with flexible overlap regions between adjacent tropomyosins is represented in the model as a system of coupled stochastic ordinary differential equations. The proposed multiscale approach provides a more detailed molecular connection between tropomyosin dynamics, the trompomyosin-actin interaction-energy landscape, and the generated force by the sarcomere.},
	doi = {10.1016/j.bpj.2019.08.003},
	author = {Aboelkassem, Yasser and Kimberly J {McCabe} and Huber, Gary and Regnier, Michael and Andrew J. {McCammon} and Andrew D. {McCulloch}}
}
@misc {aboelkassem2018turning,
	title = {Turning the Azimuthal Motions of Adjacent Tropomyosins into a Coupled N-body Problem in a Brownian Model of Cardiac Thin Filament Activation},
	howpublished = {Biophysical Journal},
	year = {2018},
	publisher = {Elsevier},
	address = {San Francisco, California/U.S.A.},
	author = {Aboelkassem, Yasser and Kimberly J {McCabe} and Huber, Gary and Sundnes, Joakim and Andrew D. {McCulloch}}
}
