title: Molecular and subcellular-scale modeling of nucleotide diffusion in the cardiac myofilament lattice.
abstract: Contractile function of cardiac cells is driven by the sliding displacement of myofilaments powered by the cycling myosin crossbridges. Critical to this process is the availability of ATP, which myosin hydrolyzes during the cross-bridge cycle. The diffusion of adenine nucleotides through the myofilament lattice has been shown to be anisotropic, with slower radial diffusion perpendicular to the filament axis relative to parallel, and is attributed to the periodic hexagonal arrangement of the thin (actin) and thick (myosin) filaments. We investigated whether atomistic-resolution details of myofilament proteins can refine coarse-grain estimates of diffusional anisotropy for adenine nucleotides in the cardiac myofibril, using homogenization theory and atomistic thin filament models from the Protein Data Bank. Our results demonstrate considerable anisotropy in ATP and ADP diffusion constants that is consistent with experimental measurements and dependent on lattice spacing and myofilament overlap. A reaction-diffusion model of the half-sarcomere further suggests that diffusional anisotropy may lead to modest adenine nucleotide gradients in the myoplasm under physiological conditions.
authors.affiliation: Department of Pharmacology, University of Arizona, California. Electronic address: pkekeneshuskey@ucsd.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kekenes-Huskey
authors.forename: Tao
authors.initials: T
authors.lastname: Liao
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Gillette
authors.forename: Johan E
authors.initials: JE
authors.lastname: Hake
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Anushka P
authors.initials: AP
authors.lastname: Michailova
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D016880:Anisotropy; D004058:Diffusion; D006868:Hydrolysis; D042541:Intracellular Space / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009210:Myofibrils / Q000378:metabolism*; D009711:Nucleotides / Q000737:chemistry / Q000378:metabolism*; D015203:Reproducibility of Results; D012518:Sarcomeres / Q000378:metabolism
chemical_list: D009711:Nucleotides; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases