Multiscale\nComputational Analysis of the Effect of\nTaxol on Microtubule Mechanics

Microtubules (MTs) are widely recognized as targets for\ncancer\ntherapies. They are directly related to unique mechanical properties,\nclosely dependent on MT architecture and tubulin molecular features.\nTaxol is known to affect tubulin interactions resulting in the stabilization\nof the MT lattice, and thus the hierarchical organization stability,\nmechanics, and function. A deeper understanding of the molecular mechanisms\nthrough which taxol modulates intertubulin interactions in the MT\nlattice, and consequently, its stability and mechanical response is\ncrucial to characterize how MT properties are regulated by environmental\nfactors, such as interacting ligands. In this study, a computational\nanalysis of the effect of taxol on the MT was performed at different\nscales, combining molecular dynamics simulation, dynamical network\nanalysis, and elastic network modeling. The results show that the\ntaxol-induced conformational differences at the M-loop region increase\nthe stability of the lateral interactions and the amount of surface\nin contact between laterally coupled tubulins. Moreover, the conformational\nrearrangements in the taxane binding site result in a different structural\ncommunication pattern. Finally, the different conformation of the\ntubulin heterodimers and the stabilized lateral interactions resulted\nin a tendency toward higher deformation of the vibrating MT in the\npresence of taxol. Overall, this work provides additional insights\ninto taxol-induced stabilization and relates the conformational changes\nat the tubulin level to the MT mechanics. Besides providing useful\ninsights into taxol effect on MT mechanics, a methodological framework\nthat could be used to characterize the effects of other MT stabilizing\nagents is presented.