CAREER: Multiscale Structural and Dynamic Modeling of Kinesin-Microtubule Motor System

智力上的优点。 驱动蛋白是一类分子马达，其通过水解三磷酸腺苷而沿沿着轨道运动。它们已经被广泛研究，不仅因为它们在细胞内运输中的关键作用，而且因为它们是已知最小的分子马达。当驱动蛋白通过其生化状态循环时，它经历一系列构象转变，导致弱和强微管结合亲和力之间的交替以及沿着微管轨道的定向运动。本项目的目标是通过使用新的多尺度计算机模拟技术来研究最小驱动蛋白-微管复合物的关键生化状态和构象转变。本项目将阐明驱动蛋白的生物化学活性是如何通过驱动蛋白-微管结合和分子内应变实现的，并确定参与驱动蛋白功能的关键氨基酸残基。与四位驱动蛋白专家合作，将通过使用最先进的实验技术（包括电子显微镜，荧光偏振显微镜，运动分析，诱变，光阱和瞬态动力学分析）来测试建模预测。本研究具有以下科学意义：（1）为其他与驱动蛋白相关的分子马达（如肌球蛋白和动力蛋白）的机理研究提供便利。 (2)它将提供一个强大的计算框架，为各种生物分子系统的构象动力学的有效和现实的建模。 (3)它将促进生物分子功能的计算建模和实验研究之间富有成效的相互作用。 更广泛的影响。 该项目将包括以下教育和推广部分：（1）通过物理学、生物学和计算学的多学科培训，培养新一代的计算生物物理学家;（2）通过开发“生物分子结构和动力学的多尺度建模”高级课程，将这一跨学科研究项目与研究生和本科生的教育相结合，以及用与生物医学专业学生有关的新材料加强物理学入门课程;（3）培训高中生计算机编程及其在生物物理学中的应用的推广方案;（4）通过网络服务器和在线数据库向全球研究人员传播新的计算机建模工具和成果。

Intellectual merit. Kinesins are a class of molecular motors that move along microtubule tracks powered by the hydrolysis of adenosine triphosphate. They have been extensively studied not only for their key roles in intracellular transport, but also because they are the smallest known molecular motors. As kinesin cycles through its biochemical states, it undergoes a series of conformational transitions that lead to alternation between weak and strong microtubule-binding affinity and directed movement along microtubule tracks. The objective of this project is to investigate the key biochemical states and conformational transitions of a minimal kinesin-microtubule complex by using novel multiscale computer modeling techniques. This project will elucidate how kinesin's biochemical activities are enabled by kinesin-microtubule binding and intramolecular strain, and pinpoint the key amino acid residues that are involved in kinesin function. In collaboration with four kinesin experts, the modeling predictions will be tested by using state-of-the-art experimental techniques (including electron microscopy, fluorescence polarization microscopy, motility assay, mutagenesis, optical trap, and transient kinetic assay). This project will offer the following scientific benefits: (1) It will facilitate the mechanistic studies of other molecular motors related to kinesin (such as myosin and dynein). (2) It will provide a powerful computational framework for efficient and realistic modeling of conformational dynamics of a variety of biomolecular systems. (3) It will promote fruitful interplay between computational modeling and experimental investigation of biomolecular functions. Broader impacts. This project will include the following educational and outreach components: (1) cultivation of a new generation of computational biophysicists through multidisciplinary trainings at the interface of physics, biology and computing; (2) integration of this interdisciplinary research project with the education of graduate and undergraduate students through the development of an advanced course on "multiscale modeling of biomolecular structures and dynamics", and the enhancement of introductory physics courses with new materials relevant to students in biomedical majors; (3) outreach programs for the training of high school students in computer programming and its applications to biophysics; (4) dissemination of new computer modeling tools and results to global researchers via a web server and an online database.