Tubulin Isotypes And Their Role In Microtubule Dynamic Instability, Implications For Modeling And Rational Design Of Inhibitors

The structural protein, β-tubulin is the target for a number of anti- mitotic compounds that bind to and inhibit microtubule dynamics, leading to apoptosis in all dividing cells. The existence of several isotypes of β- tubulin, coupled with their varied distribution throughout different organisms provides a platform upon which to construct novel agents, which are able to differentiate between cell types. Several examples of compounds that perturb microtubule dynamics, such as paclitaxel, are currently some of the most effective drugs used in cancer chemotherapy. Additionally, MT disrupting agents such as the dinitroanilines, disrupt plant but not animal microtubules and are therefore useful herbicides. However, even with their wide use and important function, the method of action of MT disrupting compounds is unknown. We have performed homology modeling on approximately 500 α- and β-tubulin sequences and identified an expected global, structural similarity of tubulin monomers. We have been able to calculate discernable differences in several properties, including their net electric charge, volume, surface area, electric dipole moment and dipole vector orientation. These are properties that may influence the functional characteristics of individual tubulin monomers, thereby resulting in a global effect on microtubule stability and assembly kinetics.