@misc {27607,
	title = {Multiscale modelling determines mechanisms of action for 2{\textquoteright}-deoxy-ATP, a myosin activating therapeutic for heart failure},
	howpublished = {VPH 2020, Paris, France (Virtual)},
	year = {2020},
	publisher = {VPH 2020},
	author = {Kimberly J {McCabe} and Aboelkassem, Yasser and Teitgen, Abigail and Regnier, Michael 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 {26463,
	title = {A Markov State Model of the Sarcomere to Explain the  Effects of dATP on Cardiac Contraction},
	year = {2018},
	address = {Biophysical Society 62nd Annual Meeting, San Francisco CA},
	abstract = {2-deoxy-ATP is a naturally occurring homolog of ATP known to increase force production, enhance crossbridge cycling speed, and accelerate the removal of Ca2+ from the cytoplasm during cardiac muscle cell relaxation. At low ratios of dATP to ATP in cardiomyocytes, steady state force has been shown to increase nonlinearly at physiological [Ca2+]1. The purpose of this study is to discover specific mechanisms by which dATP alters myosin dynamics within the sarcomere using multiscale computational modeling. We have developed a comprehensive mechanistic Monte Carlo Markov State model of rat sarcomere contraction which includes cooperativity in both thin filament activation and crossbridge cycling through nearest-neighbor Tropomyosin (Tm) interactions as well as cross bridge attachment effect on neighboring myosin on the thick filament. This novel sarcomere model was used to test the effects of dATP on contractility within the sarcomere.\&nbsp; We combined experimental data on the subcellular, cellular, and organ level as well as Molecular Dynamics (MD) data to parameterize and validate the model. We tested combinations of 4 possible kinetic transitions in which dATP is hypothesized to affect crossbridge cycling and tested various degrees of cooperativity in the system to find a likely combination of mechanisms by which dATP affects contraction.},
	author = {Kimberly J {McCabe} and Aboelkassem, Yasser and Dewan, Sukriti and Regnier, Michael and Andrew D. {McCulloch}}
}
@article {26458,
	title = {Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants{\textemdash}Genotype to Cellular Phenotype},
	journal = {Frontiers in Physiology},
	volume = {14},
	number = {151},
	year = {2017},
	month = {03/2017},
	publisher = {Frontiers in Physiology},
	doi = {10.3389/fphys.2017.00151},
	url = {http://journal.frontiersin.org/article/10.3389/fphys.2017.00151/fullhttp://journal.frontiersin.org/article/10.3389/fphys.2017.00151/full},
	author = {Dewan, Sukriti and Kimberly J {McCabe} and Regnier, Michael and Andrew D. {McCulloch}}
}
@article {26459,
	title = {Molecular Effects of cTnC DCM Mutations on Calcium Sensitivity and Myofilament Activation{\textemdash}An Integrated Multiscale Modeling Study},
	journal = {The Journal of Physical Chemistry B},
	volume = {120},
	year = {2016},
	month = {08/2016},
	pages = {8264 - 8275},
	publisher = {The Journal of Physical Chemistry B},
	issn = {1520-6106},
	doi = {10.1021/acs.jpcb.6b01950},
	url = {http://pubs.acs.org/doi/10.1021/acs.jpcb.6b01950http://pubs.acs.org/doi/pdf/10.1021/acs.jpcb.6b01950},
	author = {Dewan, Sukriti and Kimberly J {McCabe} and Regnier, Michael and Andrew D. {McCulloch} and Lindert, Steffen}
}
