Mechanochemical Energy Transduction in Protein Motors

三磷酸腺苷是所有活细胞中普遍存在的化学能量分子。三磷酸腺苷驱动的蛋白质马达在许多细胞功能中起着核心作用。例如，在有丝分裂过程中，肌动蛋白驱动细胞内的囊泡运输并移动染色体；肌球蛋白驱动肌肉收缩，v-ATPase调节细胞内的酸性。了解ATP驱动的马达的工作原理对于了解细胞内蛋白质的运输和细胞运动至关重要。结构研究提供了马达蛋白质的原子细节，并揭示了更多与它们催化的化学反应相关的信息。目前的实验技术允许以皮牛顿精度测量单个蛋白质马达的力和以纳米分辨率测量运动。这些进展，再加上数学建模和计算机能力的进步，使得以前所未有的细节探索分子马达中的机械力化学能量传递成为可能。在这个项目中，研究人员和同事们研究了在之前的F1 ATPase研究中出现的数学和物理问题。他们了解蛋白质马达应该如何建模的分子细节，以及什么数学公式适合对它们进行建模。特别是，本研究重点研究了ATP水解循环中催化部位的力产生机制。这一关键过程的解决将阐明这种由ATP驱动的马达的工作原理，也可能是其他蛋白质马达的工作原理。为了适应更复杂的建模，研究人员开发了分析蛋白质结构和求解复杂模型方程的方法。这些研究的结果为建立肌球蛋白和运动蛋白二聚体中的机械力化学能量转导模型奠定了基础。该方法是利用随机微分方程对电机的连续随机运动进行建模，并将其与离散马尔科夫过程所描述的化学反应相耦合。根据基本物理原理、结构数据、生化和生物物理测量建立模型方程，然后对这些方程进行数值分析。人们希望，这将导致对ATP驱动电机的统一看法。为了促进生物技术领域的快速发展，有必要从实验结果中推断出生物系统的简明机制。这需要应用数学和物理科学的基本原理。这个跨学科项目的目的是研究蛋白质利用化学能产生机械力的机制。反过来，这些力量驱动着生命所必需的各种细胞过程。在所有活细胞中，普遍存在的化学能分子是三磷酸腺苷。三磷酸腺苷是用从食物中提取的能量产生的，每个细胞的寿命都取决于由三磷酸腺苷提供动力的过程。例如，肌肉收缩直接由ATP蛋白马达肌球蛋白驱动。因此，理解三磷酸腺苷蛋白马达的工作原理是理解细胞寿命的核心。

Wang0077971 ATP (adenosine triphosphate) is the universal chemicalenergy molecule in all living cells. ATP driven protein motorsplay a central role in many cell functions. For example, kinesindrives intracellular vesicle transportation and moves chromosomesduring mitosis; myosin drives muscle contraction, and theV-ATPases regulate intracellular acidity. Understanding theoperating principles of the ATP driven motors is crucial tocomprehending intracellular protein transport and cell motility.Structural studies are providing the atomic details of motorproteins, and are revealing more information about theconformational changes associated with the chemical reactionsthey catalyze. Current experimental technologies permit measuringforces of a single protein motor with piconewton precision andmotions with nanometer resolution. These advances, along withadvances in mathematical modeling and computer power, make itpossible to explore the mechanochemical energy transduction inmolecular motors in unprecedented detail. In this project, theinvestigator and colleagues pursue the mathematical and physicalissues that arose in the previous studies of F1 ATPase. Theseconcern the molecular details of how protein motors should bemodeled and what mathematical formulations are adequate formodeling them. In particular, the study focuses on the mechanismof force generation at the catalytic site during the ATPhydrolysis cycle. Resolution of this key process will illuminatethe operating principles of this ATP driven motor, and likelyother protein motors as well. To accommodate more sophisticatedmodeling, the investigator develops methods for analyzing proteinstructures and solving complex model equations. The results ofthese studies set the stage for modeling the mechanochemicalenergy transduction in myosin and kinesin dimers. The approach isto model the continuous stochastic motion of the motor usingstochastic differential equations and couple these to thechemical reactions described by discrete Markov processes. Themodel equations are constructed from basic physical principles,structural data, and biochemical and biophysical measurements.These equations are then analyzed numerically. The hope is thatthis will lead to a unified view of ATP driven motors. To facilitate the fast growing field of biotechnology, it isnecessary to deduce concise mechanisms for biological systemsfrom experimental results. This requires the application offundamental principles from the mathematical and physicalsciences. The purpose of this interdisciplinary project is tostudy the mechanisms by which proteins use chemical energy togenerate mechanical forces. In turn, these forces drive a widevariety of cellular processes essential to life. In all livingcells, the universal chemical energy molecule is ATP (adenosinetriphosphate). ATP is produced using the energy extracted fromfood, and the life of every cell depends on processes that arepowered by ATP. For example, muscle contraction is directlydriven by the ATP protein motor myosin. Therefore, understandingthe operating principles of the ATP protein motors is central tocomprehending the life of cells.