Multi-Scale Modeling of Microtubule Dynamics and the Regulation by Microtubule-Targeting Agents
2020-01
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Multi-Scale Modeling of Microtubule Dynamics and the Regulation by Microtubule-Targeting Agents
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2020-01
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Microtubules (MTs) serve to facilitate vital cellular functions, such as chromosome segregation during mitosis and synaptic plasticity. MTs self-assemble via “dynamic instability,” in which the dynamic plus ends switch stochastically between alternating phases of polymerization and depolymerization. A key question in the field is what are the atomistic origins of this switching, i.e., what is different between the GTP- and GDP-tubulin states that enables MT growth and shortening, respectively? More generally, MTs are a great example of a complex biological system with spatial and temporal scales ranging from atomistic interactions such as GTP hydrolysis to cell-level behavior such as response to MT dynamics during mitotic progression. To understand a complex biological system behavior, a key challenge is connecting together the vast range of theoretical frameworks across length- and time scales. At the same time, MT interactions with associated proteins and binding agents, such as chemotherapy drugs, can strongly affect this dynamic process through molecular mechanisms that remain to be elucidated. The work in this dissertation integrates multiscale computational modeling with high resolution experimental observations to understand the molecular mechanism underlying MT dynamic instability and the regulation of dynamics by a well-established microtubule-targeting agent (MTA), colchicine. First, we develop a multi-scale modeling framework in which molecular dynamics (MD) are performed to investigate the interaction potential energies of tubulin-tubulin heterodimers, then, those results will be incorporated into Brownian dynamics (BD) simulations to study the kinetics of dimers assembly into MT lattice, and finally, thermo-kinetic and mechanochemical modeling of MT assembly, with inputs from MD and BD simulations, provide an insight into individual MT dynamics and details about MT tip structures. The model results point to a nucleotide-independent lateral bond of ~4 kBT, a nucleotide-dependent longitudinal bond of ~9 and ~5 kBT (∆∆G_long^0≈ 4 kBT) for GTP- and GDP-dimers, respectively and a radial bending angle preference (~1.5 kBT) for GDP-dimers. Furthermore, the framework informs us on how a well-known MTA, colchicine, affects MT dynamics. We found that colchicine binds mainly to free tubulin and sub-stoichiometrically poisons the end of protofilaments (PFs) through a copolymerization mechanism by which tubulin-colchicine (TC) complexes reduce the affinity of the PF for further tubulin addition and reinforce tubulin-tubulin lateral bond, a mechanism entirely distinct from that of paclitaxel or vinblastine.. In summary, this dissertation advances our knowledge about the molecular mechanism that drives dynamic instability and its regulation by MTAs within the context of cellular biology through a multi-scale approach and can be used for the development of more effective cancer therapeutic agents.
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University of Minnesota Ph.D. dissertation. January 2020. Major: Mechanical Engineering. Advisor: David Odde. 1 computer file (PDF); xiv, 162 pages.
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Hemmat, Mahya. (2020). Multi-Scale Modeling of Microtubule Dynamics and the Regulation by Microtubule-Targeting Agents. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/219311.
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