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Abstract
Microtubules (MTs), long filamentous hollow cylinders whose surface lattice structures of αβ-tubulin dimers, manipulate a variety of biological functions, maintaining structural integrity of cells, facilitating cell mitosis, adjusting placement or transport of subcellular structures. Investigating biomechanics of MTs could help gain a thorough understanding of cellular functions of MTs, and thus shed light upon human diseases and disorders associated with MT malfunctions. In this study, we have developed a multiscale computational framework, integrating all-atomistic molecular dynamics (AAMD) simulations, coarse-grained molecular dynamics (CGMD) simulations, and finite element analysis (FEA), to study biomechanics of microtubules and its complex. First, AAMD simulations have been implemented to study the energetic evolution and mechanical properties of αβ-tubulin dimers under tension, building blocks of microtubules. Results indicate that electrostatic interactions dominate intra-dimer tubulin-tubulin (IDTT) interactions. In addition, residual mutations for amino acids with net charges, namely ARG 105 on α tubulin and ASP 251 on β tubulin, can greatly improve the IDTT strength. Second, based on out from AAMD simulations, a FEM model was calibrated and the mechanical performance under different loading cases were studied. Third based on the output from AAMD simulations above, a self-organized polymer (SOP) model has been calibrated to study biomechanics of microtubule protofilaments. Results indicate that under tension, the stiffness decreases as the curvature decreases while under shear, the stiffness increases as the curvature increases. Last, based on results from AAMD simulations, a bead-spring coarse-grained model have been calibrated to study mechanical performance of axon, microtubule bundles cross-linked by microtubule associate tau proteins. Results indicate that the stress-strain responses undergo a transition from nonlinear to linear as the average microtubule length increases. Moreover, the changes of stiffness of axon versus average microtubule length can be well captured by shear-lag model. Overall, this study provides a robust simulation framework that can be used to explore biomechanics of microtubules and its complex across different temporal and spatial scales. Moreover, the research findings here help gain a deep understanding of MT functions from a mechanistic perspective and could pave a new route to treatment of brain disorders associated with MT malfunctions.