Study of conformational mobility of tubulin protein in the presence of taxol by molecular modeling methods

Fedorov, V.A.; Kholina, E.G.; Gudimchuk, N.B.; Kovalenko, I.B.

Авторы: Fedorov V.A., Kholina E.G., Gudimchuk N.B., Kovalenko I.B.
Журнал: Biophysical Reviews
Том: 15
Год издания: 2023
Издательство: Springer Verlag
Местоположение издательства: Germany
Первая страница: 1479
Последняя страница: 1479
DOI: 10.1007/s12551-023-01150-w
Аннотация: Microtubules are essential components of the cytoskeleton and play a major role in cell division. Microtubules are composed of αβ-tubulin, which assembles longitudinally into protofilaments. About 13 protofila- ments bind laterally, thereby forming a microtubule wall. Essential to microtubule function is the property of dynamic instability, the ability to spontaneously switch between microtubule growth and shortening associated with GTP binding and hydrolysis. Microtubule dynamics is regulated in vivo by a number of microtubule-associated proteins. In medicine, antimitotic chemotherapeutic agents such as taxol, which bind to and stabilize microtubules, suppress dynamic instability and prevent cell division, are widely and very successfully used. Taxol and other sta- bilizing compounds also interfere with interphase microtubules, thereby affecting many important cellular processes. Since its discovery, taxol has been the subject of many studies aimed at elucidating its mechanism of action. The molecular mechanisms of action of such drugs can be studied in silico using the molecular dynamics method.To reveal differences in the mechanical properties of tubulin protofila- ments bound to GTP, GDP, and GDP+taxol, we performed a series of computational experiments using the full atom molecular dynamics method in an explicitly specified solvent. An important improvement compared to previous calculations of the dynamics of GTP- and GDP tubulin protofilaments was the use of new data from works (Manka S.W., Moores C.A. Nat Struct Mol Biol. 2018; Zhang R et al. Proc Natl Acad Sci U S A. 2018), which for the first time determined the structures of tubulins associated with GDP and a non-hydrolyzable analogue of GTP in the composition of 13-protofilament microtu- bules. Using our previously developed method for analyzing the bend- ing angles of tubulin protofilaments (Fedorov et al., Plos Comp. Biol. 2019), based on the calculation of modified Euler angles, we evaluated the conformational mobility of GTP-, GDP-tubulins and GDP-tubulins with taxol. Taxol addition has been shown to result in changes at both intra- and inter-dimeric interfaces. The change in both the magnitude of the bending stiffness and the bending direction was evaluated in the presence of taxol.The work was performed using the equipment of the Center for Collec- tive Use of Ultra-High-Performance Computing Resources of Lomono- sov Moscow State University with the support of a grant from the Russian Science Foundation, project No. 22-74-00119.
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Study of conformational mobility of tubulin protein in the presence of taxol by molecular modeling methodsстатья Тезисы

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