“Mechanobiology of microtubule self-assembly: deciphering the physical principles behind microtubule force generation and sensing”

Host: Prof Geoff Barton

Venue: MSI , Small Lecture Theatre, SLS.

Abstract 

 At the heart of many cellular processes, microtubule filaments are responsible for actively organizing the cellular interior, enabling directed intracellular transport and providing force stroke during cell division. The latter is achieved by the mitotic spindle, primarily using microtubules that exert forces on kinetochore complexes attached to the chromosomes. Microtubules are nature’s most prominent self-assembling molecular machines and literally the quintessence of how complex physiological functions emerge from the self-assembly of simple protein 'building blocks' called tubulins. Microtubules grow by the addition of GTP-bound tubulin dimers at their flaring ends and alternate between phases of slow growth and rapid shrinkage upon hydrolyzing GTP to GDP – an astounding phenomenon called 'dynamic instability'. Notwithstanding its importance, the mechanism of dynamic instability and microtubule-driven force transduction remains elusive. Mistakes in this process can lead to severe diseases like birth defects, infertility, and tumorigenesis. Therefore, a necessary step prior to developing any new treatments is to answer a basic question: How do microtubules generate forces through directed assembly and disassembly? To this end, we used atomistic, explicit-solvent simulations to scrutinize the microsecond dynamics of complete GTP- and GDP-microtubule models. Our findings have shown that post-hydrolysis microtubules are exposed to higher activation energy barriers for straight lattice formation, which strongly reduces their probability to elongate. We further developed a minimal coarse-grained model of microtubule dynamics and parametrized it using free-energy matching with extensive all-atom simulations of tubulin oligomers and whole microtubules. Our model (1) reconciles previous contradictory measurements of microtubule forces; (2) demonstrates the importance of the spring-like elasticity of and interactions between curling tubulin oligomers at the microtubule end; (3) and shows that the flare microtubule end structure enables proper kinetochore-microtubule attachment in a hydrolysis-state dependent manner. Lastly, future perspectives of my research in the context of the mechanobiology of dynamic biological polymers will be elucidated. In particular, combining data-driven computational tools with state-of-the-art single-molecule, structural, and biochemical