@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}}
}
@inproceedings {23356,
	title = {A Markov-State Model for the Regulation of the Sarcoplasmic Reticulum Ca2+ ATPase by Phospholamban},
	journal = {Annual meeting in Biophysical society},
	volume = {106},
	year = {2014},
	month = {01/2014},
	publisher = {Elsevier},
	abstract = {Compelling evidence suggests that reduced sarcoplasmic reticulum (SR) Ca 2+ uptake via\&nbsp;the SR Ca 2+ ATPase (SERCA) is a major contributor to the development of Ca 2+ signaling\&nbsp;abnormalities in heart failure, and equally important as other known contributors to impaired\&nbsp;Ca 2+ handling.},
	author = {Peter M. {Kekenes-Huskey} and Andrew G {Edwards} and Johan Elon {Hake} and Anushka P. {Michailova} and Andrew J. {McCammon} and Andrew D. {McCulloch}}
}
@article {Simula.simula.2284,
	title = {Molecular and Subcellular-Scale Modeling of Nucleotide Diffusion in the Cardiac Myofilament Lattice},
	journal = {Biophysical Journal},
	volume = {105},
	number = {9},
	year = {2013},
	pages = {2130},
	doi = {10.1016/j.bpj.2013.09.020},
	author = {Peter M. {Kekenes-Huskey} and Liao, Tao and Andrew K. {Gillette} and Johan Elon {Hake} and Zhang, Yongjie and Anushka P. {Michailova} and Andrew D. {McCulloch} and Andrew J. {McCammon}}
}
@article {Simula.simula.1664,
	title = {Finite-Element Estimation of Protein-ligand Association Rates With Post-Encounter Effects: Applications to Calcium Binding in Troponin C and SERCA},
	journal = {Computational Science \& Discovery},
	volume = {5},
	number = {1},
	year = {2012},
	pages = {014015},
	abstract = {We introduce a computational pipeline and suite of software tools for the approximation of diffusion-limited binding based on a recently developed theoretical framework. Our approach handles molecular geometries generated from high-resolution structural data and can account for active sites buried within the protein or behind gating mechanisms. Using tools from the FEniCS library and the APBS solver, we implement a numerical code for our method and study two Ca2+-binding proteins: troponin C and the sarcoplasmic reticulum Ca2+ ATPase. We find that a combination of diffusional encounter and internal {\textquoteright}buried channel{\textquoteright} descriptions provides superior descriptions of association rates, improving estimates by orders of magnitude.},
	author = {Peter M. {Kekenes-Huskey} and Andrew K. {Gillette} and Johan Elon {Hake} and Andrew J. {McCammon}}
}
@misc {Simula.simula.1428,
	title = {Modeling Calcium Dynamics in Realistic Rabbit Ventricular Myocytes With Several Transverse Tubules},
	year = {2012},
	author = {Peter M. {Kekenes-Huskey} and Johan Elon {Hake} and Cheng, Yuhui and Michael J. {Holst} and Frank B. {Sachse} and John H. {Bridge} and Andrew D. {McCulloch} and Andrew J. {McCammon} and Anushka P. {Michailova}}
}
@misc {Simula.simula.1410,
	title = {Modeling Calcium Sparks in a Three-Dimensional Reconstruction of a Cardiac Calcium Release Unit},
	year = {2012},
	author = {Johan Elon {Hake} and Andrew G {Edwards} and Yu, Z. and Peter M. {Kekenes-Huskey} and Anushka P. {Michailova} and Andrew J. {McCammon} and Michael J. {Holst} and Hoshijima, Masahiko and Andrew D. {McCulloch}}
}
@article {Simula.simula.1318,
	title = {Modeling Cardiac Calcium Sparks in a Three-Dimensional Reconstruction of a Calcium Release Unit},
	journal = {The Journal of Physiology},
	volume = {590},
	number = {18},
	year = {2012},
	month = {Sept},
	pages = {4403-4422},
	author = {Johan Elon {Hake} and Andrew G {Edwards} and Yu, Z. and Peter M. {Kekenes-Huskey} and Anushka P. {Michailova} and Andrew J. {McCammon} and Michael J. {Holst} and Hoshijima, Masahiko and Andrew D. {McCulloch}}
}
@article {Simula.simula.1722,
	title = {Modeling Effects of L-Type Ca2+ Current and Na+-Ca2+ Exchanger on Ca2+ Trigger Flux in Rabbit Myocytes With Realistic T-Tubule Geometries},
	journal = {Frontiers in Physiology},
	volume = {3},
	year = {2012},
	pages = {351},
	keywords = {Workshop},
	author = {Peter M. {Kekenes-Huskey} and Cheng, Yuhui and Johan Elon {Hake} and Frank B. {Sachse} and John H. {Bridge} and Michael J. {Holst} and Andrew J. {McCammon} and Andrew D. {McCulloch} and Anushka P. {Michailova}}
}
@article {Chen-2012-15002,
	title = {Multi-Scale Continuum Modeling of Biological Processes: From Molecular Electro-Diffusion to Sub-Cellular Signaling Transduction},
	journal = {Computational Science \& Discovery},
	volume = {5},
	number = {1},
	year = {2012},
	pages = {015002},
	keywords = {Conference},
	author = {Cheng, Y. and Peter M. {Kekenes-Huskey} and Johan Elon {Hake} and Michael J. {Holst} and Andrew J. {McCammon} and Anushka P. {Michailova}}
}
@misc {Simula.simula.966,
	title = {Contributions of Multiple T-Tubules and Membrane Ca2+ Flux Localization to Sub-Cellular Ca2+ Signaling in Rabbit Ventricular Myocytes},
	year = {2011},
	author = {Peter M. {Kekenes-Huskey} and Johan Elon {Hake} and Cheng, Yuhui and Sachse, Frank and Bridge, John and Andrew J. {McCammon} and Anushka P. {Michailova}}
}
@misc {Simula.simula.968,
	title = {Contributions of Structural T-Tubule Heterogeneities and Membrane Ca2+ Flux Localization to Local Ca2+ Signaling in Rabbit Ventricular Myocytes},
	year = {2011},
	author = {Peter M. {Kekenes-Huskey} and Johan Elon {Hake} and Cheng, Yuhui and Sachse, Frank and Bridge, John and Andrew J. {McCammon} and Anushka P. {Michailova}}
}
@article {Simula.sc.1184,
	title = {Numerical Analysis of Ca2+ Signaling in Rat Ventricular Myocytes With Realistic Transverse-Axial Tubular Geometry and Inhibited Sarcoplasmic Reticulum},
	journal = {PLoS Computational Biology},
	volume = {6},
	number = {10},
	year = {2010},
	pages = {e1000972},
	publisher = {PubMed Central},
	doi = {doi:10.1371/journal.pcbi.1000972},
	author = {Cheng, Y. and Yu, Z. and Hoshijima, M. and Michael J. {Holst} and Andrew D. {McCulloch} and Andrew J. {McCammon} and Anushka P. {Michailova}}
}
@article {Simula.simula.2660,
	title = {Computational Analysis of the Interactions Between the Angiogenesis Inhibitor PD173074 and Fibroblast Growth Factor Receptor 1},
	journal = {Journal of Theoretical and Computational Chemistry},
	volume = {2},
	number = {1},
	year = {2003},
	pages = {43-56},
	author = {T{\o}ndel, Kristin and Chung F. {Wong} and Andrew J. {McCammon}}
}
