Three-dimensional stochastic model of actin-myosin binding in the sarcomere lattice.
Three-dimensional stochastic model of actin-myosin binding in the sarcomere lattice.
复制标题
DOI：
10.1085/jgp.201611608
复制
发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Geeves MA
中科院分区：
文献类型：
--
作者：
Mijailovich SM;Kayser-Herold O;Stojanovic B;Nedic D;Irving TC;Geeves MA
例如，横纹肌的细胞收缩模型通常涉及质量作用动力学。米贾洛维奇等人。在蒙特卡罗平台 MUSICO 中实现空间明确的肌动球蛋白相互作用，并显示肌球蛋白束缚对其他生物参数的影响程度。三维 (3-D) 空间中的分子束缚对双分子结合动力学的影响很少得到解决，并且只是偶尔纳入细胞运动模型中。能够定量确定这种效应的最简单的系统是横纹肌的 3-D 肌节晶格，其中粗丝中的拴系肌球蛋白只能与肌动蛋白丝上相对少量的可用位点结合，这些位点位于肌球蛋白头部热运动的有限范围内。在这里，我们将空间明确的肌动球蛋白相互作用实现到多尺度蒙特卡罗平台 MUSICO 中，具体定义了束缚肌球蛋白的几何约束如何调节肌动球蛋白循环中的状态转换率。模拟提供了与肌动蛋白上位点结合的肌球蛋白的分布，确保了相互作用的肌球蛋白和肌动蛋白单体的数量的保守，最重要的是，束缚的肌球蛋白分子的行为偏离了与肌动蛋白不受约束的肌球蛋白相互作用。此外，MUSICO 还确定每个肌动球蛋白循环状态下的跨桥数量、每个肌球蛋白丝附着的跨桥的力和数量、跨桥力的范围并考虑能量消耗。在宏观尺度上，MUSICO 模拟显示，与两个最简单的质量作用动力学模型相比，预测的力-速度曲线以及长度阶跃变化后早期力恢复阶段的响应存在巨大差异。这些差异的根源在于肌球蛋白结合的不同通量和相应的瞬时跨桥分布，并定量地反映了所有质量作用动力学模型中数学描述的主要缺陷。因此，这种新方法表明，实验数据的准确重述需要与质量作用动力学模型中通常使用的结合率、肌动球蛋白状态数和跨桥弹性显着不同，以正确描述系留分子的生化反应及其相互作用能量学。
Models of cellular contraction, for example, in striated muscle, usually involve mass action kinetics. Mijailovich et al. implement spatially explicit actomyosin interactions in the Monte Carlo platform MUSICO and show the extent to which myosin tethering affects other biological parameters. The effect of molecule tethering in three-dimensional (3-D) space on bimolecular binding kinetics is rarely addressed and only occasionally incorporated into models of cell motility. The simplest system that can quantitatively determine this effect is the 3-D sarcomere lattice of the striated muscle, where tethered myosin in thick filaments can only bind to a relatively small number of available sites on the actin filament, positioned within a limited range of thermal movement of the myosin head. Here we implement spatially explicit actomyosin interactions into the multiscale Monte Carlo platform MUSICO, specifically defining how geometrical constraints on tethered myosins can modulate state transition rates in the actomyosin cycle. The simulations provide the distribution of myosin bound to sites on actin, ensure conservation of the number of interacting myosins and actin monomers, and most importantly, the departure in behavior of tethered myosin molecules from unconstrained myosin interactions with actin. In addition, MUSICO determines the number of cross-bridges in each actomyosin cycle state, the force and number of attached cross-bridges per myosin filament, the range of cross-bridge forces and accounts for energy consumption. At the macroscopic scale, MUSICO simulations show large differences in predicted force-velocity curves and in the response during early force recovery phase after a step change in length comparing to the two simplest mass action kinetic models. The origin of these differences is rooted in the different fluxes of myosin binding and corresponding instantaneous cross-bridge distributions and quantitatively reflects a major flaw of the mathematical description in all mass action kinetic models. Consequently, this new approach shows that accurate recapitulation of experimental data requires significantly different binding rates, number of actomyosin states, and cross-bridge elasticity than typically used in mass action kinetic models to correctly describe the biochemical reactions of tethered molecules and their interaction energetics.
登录
查看更多内容
影响因子：
10.8
作者：
Burgoyne T;Muhamad F;Luther PK
通讯作者：
Luther PK
影响因子：
5.5
作者：
FORD, LE;HUXLEY, AF;SIMMONS, RM
通讯作者：
SIMMONS, RM
影响因子：
4.4
作者：
Eyring, H
通讯作者：
Eyring, H
影响因子：
3.4
作者：
HUNT, AJ;GITTES, F;HOWARD, J
通讯作者：
HOWARD, J
影响因子：
3.4
作者：
Evans, E;Ritchie, K
通讯作者：
Ritchie, K