Insight into Nucleation of Microtubules to Realize Novel Drug Targets

Abstract

Microtubules are highly dynamic cytosketal polymers that are built up of heterodimers of and#945; and and#946; tubulin proteins that self assembles in a head to tail fashion to make long protofilaments Generally, thirteen of these protofilaments then assemble laterally to form a sheet which then folds into a hollow cylinder to form microtubule The linear arrangement of and#945;and#946; tubulin also gives a polarity to resulting microtubules that display dynamic instability in that they continually undergo lengthening and shortening at both ends more rapidly at one end, named the plus end, than the other slower minus end Microtubules are key component of mitotic spindle apparatus that is necessary for the alignment and subsequent segregation of duplicated chromosomes into daughter cells during cell division They play a vital role in many other cellular functions including cell polarity, cell motility, transport of intracellular organelles and maintenance of the overall cellular morphology Such a myriad of roles calls for a very rapid reorganization of microtubules and#947; tubulin is essential for the nucleation and organization of mitotic microtubules in dividing cells It is localized at the microtubule organizing centre and experimentally observed to interact with the minus end of microtubules The most well accepted hypothesis for the initiation of microtubule polymerization is that and#945;and#946; tubulin dimers add onto a and#947; tubulin ring complex and#947;TuRC, in which adjacent and#947; tubulin subunits bind to the underlying non tubulin components of the and#947;TuRC This template thus determines the resulting microtubule lattice In this study we have used molecular modelling and molecular dynamics simulations, combined with computational MM PBSA MM GBSA methods, to determine the extent of the lateral atomic interaction between two adjacent and#947; tubulins