Bioengineering Analysis of Muscle Mechanics & Metabolism

描述(由申请人提供)： 利用工程分析的方法，我们将开发一个结合当前分子结构、生化能量学和收缩动力学知识来描述肌肉收缩的计算平台。我们的目标是开发一个全面的模型，该模型可用于(1)产生关于收缩蛋白肌球蛋白和肌动蛋白功能的新的机制假说，以及(2)定量评估辅助蛋白和调节蛋白在收缩中的作用。一旦开发出来，该模型将成为研究肌肉收缩的强大分析和预测工具。目前，由于(1)肌动蛋白和肌球蛋白细丝的延伸性和(2)钙调节收缩的并发症，尚无收缩模型可解释。肌球蛋白头与肌动蛋白相互作用时，肌球蛋白头部的应力和应变会发生变化，细丝的伸长性会导致载荷传递不均匀。必须考虑这些影响，才能理解跨桥作用力如何影响肌动球蛋白ATPase循环中的化学转变，反之亦然。此外，对钙调控的定量理解将允许(1)更准确地预测特定调控事件的宏观力学和能量后果，(2)从潜在的分子过程角度更准确地解释宏观事件。本BRP通过一种跨越工程科学、计算科学和生物物理学的多学科方法来解决这些问题，并完全依赖于基本原则。我们的团队将开发一个收缩模型，该模型集成了一个关键缺失元素-细丝延伸性-以及在理解(1)肌球蛋白的生化状态；(2)肌球蛋白ATP水解循环中的过渡速率常数；(3)肌球蛋白分子马达在粗细丝格(肌节)中的功能；以及(4)钙对肌球蛋白结合的调节方面的最新进展。最初，该模型将把概率或随机的肌动球蛋白结合动力学与有限元分析相结合(无论是连续的还是空间离散的，与粗丝和细丝的周期一致)。然后，该模型将被改进，以解释平滑肌收缩，包括能量高效的闩锁状态和参与收缩调节的蛋白质的行动。这里开发的计算模型将引用适用于肌动肌球蛋白相互作用周期的统一原则，无论肌肉类型如何，但将具有足够的灵活性来解释不同肌肉类型的收缩动力学和收缩调节。收缩的定量模型对于理解一系列症状和疾病的分子基础是至关重要的，例如哮喘的呼吸道狭窄和心力衰竭的心脏和骨骼肌的虚弱。

DESCRIPTION (provided by applicant): Using the methods of engineering analysis, we will develop a computational platform that incorporates current knowledge of molecular structure, biochemical energetics, and contraction kinetics to describe muscle contraction. Our goal is to develop a comprehensive model that can be used to (1) generate new mechanistic hypotheses concerning the functions of the contractile proteins myosin and actin and (2) quantitatively evaluate the roles of accessory and regulatory proteins in contraction. Once developed, the model will be a powerful analytical and predictive tool in studies of muscle contraction. Presently, no models of contraction account for complications due to both (1) extensibility of the actin and myosin filaments and (2) Ca2+ regulation of contraction. Filament extensibility results in non-uniform load transfer along the thick and thin filaments, which introduces variability in the stress and strain of the myosin heads during their interactions with actin. These effects must be taken into account to understand how cross-bridge forces affect chemical transitions in the actomyosin ATPase cycle and vice versa. Further, quantitative understanding of Ca 2+ regulation will allow (1) more accurate predictions of the macroscopic mechanical and energetic consequences of specific regulatory events and (2) more accurate explanations of macroscopic events in terms of underlying molecular processes. This BRP addresses these problems via a multidisciplinary approach that spans engineering science, computational science, and biophysics and rests entirely upon first principles. Our team will develop a model of contraction that integrates a critical missing element-filament extensibility-with recent advances in understanding the (1) biochemical states of myosin; (2) transitional rate constants in the actomyosin ATP hydrolysis cycle; (3) function of myosin molecular motors in the thick and thin filament lattice (sarcomere); and (4) Ca 2+ regulation of myosin binding. Initially, the model will combine probabilistic or stochastic actomyosin binding kinetics with finite element analysis (either continuous or spatially discrete consistent with the periodicities of the thick and thin filaments). The model will then be refined to explain smooth muscle contraction, including the energetically efficient latch state and the actions of proteins involved in the regulation of contraction. The computational model developed here will invoke unifying principles that apply to the actomyosin interaction cycle regardless of muscle type but will have sufficient flexibility to account for contraction kinetics and regulation of contraction in different muscle types. Quantitative modeling of contraction is ultimately essential for understanding the molecular basis for a wide range of syndromes and diseases, such as airway narrowing in asthma and weakness of both heart and skeletal muscles in heart failure.