Computational Investigations of the Biomechanics of Protein-protein Interactions Involved in the Control of Microtubule Disassembly

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The conversion of energy into mechanical work and the conversion of physical force into biochemical signals lies at the heart of cellular function, and both of these processes are mediated by protein-protein interactions. Understanding the pathways and mechanisms that couple the action of forces from the physical world with changes in cellular and molecular conformations is a challenging ongoing effort in modern biology. This project addresses, through computational modeling at multiple scales within the cell, the behavior of microtubules and associated proteins which are components of the dynamic structure (the cytoskeleton) which controls cell shape and responds to external physical forces on the cell. This project will elucidate underlying principles that govern the behavior of cellular systems with crucial roles in transducing mechanical forces and that can be used to design bio-inspired materials with enhanced stability and fatigue behavior. The project will provide education and training of undergraduate and graduate students in computational biophysical chemistry and increase the participation of groups underrepresented in science through the outreach "Girls in Science and Technology Program" at local middle-schools and through research experience opportunities for freshmen students participating in the "Women in Science and Engineering" program at the University of Cincinnati. The results of the project will be disseminated to the general public by the investigator and students through publications, conference presentations, and visits to local schools. The project will address the role of structural fatigue in microtubule disassembly. The computer simulations proposed here will reach the long time- and length-scales required to investigate the mechanical behavior of microtubules and will supply details about the changes that accompany the formation of defects in the lattice. Lattice defects are high-affinity binding sites for proteins involved in the disassembly of microtubules and modulate the macroscopic elastic behavior addressed experimentally in this project. The project will also determine the origin of molecular-level changes in microtubule filament disassembly induced by the mechanical action of microtubule-associated proteins. Multiscale modeling of filament and microtubule-associated protein complexes will be used in forced disassembly simulations to determine molecular-level information about the role of kinesins in inducing highly curved intermediates during microtubule depolymerization. The combination of simulations and experiments in this project will establish the link between microtubule-severing protein interactions and the nature of intermediate steps of the severing process.