Dataset Information

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.

SUBMITTER: Kekenes-Huskey PM

PROVIDER: S-EPMC3835335 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Molecular and subcellular-scale modeling of nucleotide diffusion in the cardiac myofilament lattice.

Kekenes-Huskey Peter M PM Liao Tao T Gillette Andrew K AK Hake Johan E JE Zhang Yongjie Y Michailova Anushka P AP McCulloch Andrew D AD McCammon J Andrew JA

Biophysical journal 20131101 9

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 ...[more]

PMID: 24209858

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Project description:During muscle contraction, myosin motors anchored to thick filaments bind to and slide actin thin filaments. These motors rely on energy derived from ATP, supplied, in part, by diffusion from the sarcoplasm to the interior of the lattice of actin and myosin filaments. The radial spacing of filaments in this lattice may change or remain constant during contraction. If the lattice is isovolumetric, it must expand when the muscle shortens. If, however, the spacing is constant or has a different pattern of axial and radial motion, then the lattice changes volume during contraction, driving fluid motion and assisting in the transport of molecules between the contractile lattice and the surrounding intracellular space. We first create an advective-diffusive-reaction flow model and show that the flow into and out of the sarcomere lattice would be significant in the absence of lattice expansion. Advective transport coupled to diffusion has the potential to substantially enhance metabolite exchange within the crowded sarcomere. Using time-resolved x-ray diffraction of contracting muscle, we next show that the contractile lattice is neither isovolumetric nor constant in spacing. Instead, lattice spacing is time varying, depends on activation, and can manifest as an effective time-varying Poisson ratio. The resulting fluid flow in the sarcomere lattice of synchronous insect flight muscles is even greater than expected for constant lattice spacing conditions. Lattice spacing depends on a variety of factors that produce radial force, including cross-bridges, titin-like molecules, and other structural proteins. Volume change and advective transport varies with the phase of muscle stimulation during periodic contraction but remains significant at all conditions. Although varying in magnitude, advective transport will occur in all cases in which the sarcomere is not isovolumetric. Akin to "breathing," advective-diffusive transport in sarcomeres is sufficient to promote metabolite exchange and may play a role in the regulation of contraction itself.

Dataset Information

Molecular and subcellular-scale modeling of nucleotide diffusion in the cardiac myofilament lattice.

Publications

Molecular and subcellular-scale modeling of nucleotide diffusion in the cardiac myofilament lattice.

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