CAREER: Multiscale Structural and Dynamic Modeling of Kinesin-Microtubule Motor System
Wenjun Zheng Principal Investigator
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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. <br/><br/>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.