Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Poster Abstracts

MULTISCALE MODELING OF THE EFFECTS OF 2-DEOXY-ATP ON SERCA FUNCTION Abigail E Teitgen 1 ; Marcus Hock 1 ; Kimberly J McCabe 2 ; Gary Huber 3 ; Rommie E Amaro 3 ; J. Andrew McCammon 3 ; Michael Regnier 4 ; Andrew D McCulloch 1 ; 1 University of California, San Diego, Bioengineering, San Diego, CA, USA 2 Simula Research Laboratory, Computational Physiology, Oslo, Norway 3 University of California, San Diego, Chemistry and Biochemistry, San Diego, CA, USA 4 University of Washington, Bioengineering, Seattle, WA, USA 2-deoxy-ATP, a naturally occurring near analog of ATP, is a myosin activator that has been demonstrated to increase contractile force and improve ventricular function, including increased relaxation. Calcium transients of cardiomyocytes with elevated levels of dATP show faster decay, but the mechanisms behind this are unknown. We hypothesize that dATP acts on the sarcoendoplasmic reticulum calcium transport ATPase (SERCA2a) pump to accelerate calcium sequestration into the sarcoplasmic reticulum during cardiac relaxation. In this work, we utilized a multiscale computational modeling approach to assess the effects of dATP on SERCA at the molecular and cellular levels. We conducted 200 ns Gaussian accelerated Molecular Dynamics simulations of human cardiac SERCA2a in the apo E1 state, and with ATP and dATP bound. Conformational clustering led to distinct representative structures for ATP- and dATP-bound SERCA. Specifically, dATP showed more stable contacts in the nucleotide binding pocket, and was positioned to allow for faster phosphorylation of the pump than ATP. dATP binding also led to increased closure of the A and N cytosolic domains, suggesting that dATP enhances SERCA pump function via the E1-ATP to E1-ADP transition. dATP also stabilized key transmembrane helices, with greater distances observed between residues in the calcium entry pathway and binding site I. Brownian dynamics (BD) simulations were utilized to assess differences in nucleotide binding kinetics between ATP and dATP to SERCA. Additional BD simulations were used to investigate differences in the rate of calcium binding to ATP- and dATP-bound SERCA. We integrated these results in a model of cardiomyocyte calcium dynamics and found that the molecular level effects of dATP on SERCA contributed to the increased calcium transient decay rate observed experimentally. This study provides the first biophysical evidence of mechanistic differences in SERCA pump function caused by dATP.

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