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Probing the origin of tubulin rigidity with molecular simulations.

ABSTRACT: Tubulin heterodimers are the building blocks of microtubules, a major component of the cytoskeleton, whose mechanical properties are fundamental for the life of the cell. We uncover the microscopic origins of the mechanical response in microtubules by probing features of the energy landscape of the tubulin monomers and tubulin heterodimer. To elucidate the structures of the unfolding pathways and reveal the multiple unfolding routes, we performed simulations of a self-organized polymer (SOP) model of tubulin. The SOP representation, which is a coarse-grained description of chains, allows us to perform force-induced simulations at loading rates and time scales that closely match those used in single-molecule experiments. We show that the forced unfolding of each monomer involves a bifurcation in the pathways to the stretched state. After the unfolding of the C-term domain, the unraveling continues either from the N-term domain or from the middle domain, depending on the monomer and the pathway. In contrast to the unfolding complexity of the monomers, the dimer unfolds according to only one route corresponding to the unraveling of the C-term domain and part of the middle domain of beta-tubulin. We find that this surprising behavior is due to the viscoelastic properties of the interface between the monomers. We map precise features of the complex energy landscape of tubulin by surveying the structures of the various metastable intermediates, which, in the dimer case, are characterized only by changes in the beta-tubulin monomer.

SUBMITTER: Dima RI

PROVIDER: S-EPMC2572946 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Probing the origin of tubulin rigidity with molecular simulations.

Dima Ruxandra I RI Joshi Harshad H

Proceedings of the National Academy of Sciences of the United States of America 20081007 41

Tubulin heterodimers are the building blocks of microtubules, a major component of the cytoskeleton, whose mechanical properties are fundamental for the life of the cell. We uncover the microscopic origins of the mechanical response in microtubules by probing features of the energy landscape of the tubulin monomers and tubulin heterodimer. To elucidate the structures of the unfolding pathways and reveal the multiple unfolding routes, we performed simulations of a self-organized polymer (SOP) mod ...[more]

PMID: 18840679

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Project description:Tubulin isotypes are found to play an important role in regulating microtubule dynamics. The isotype composition is also thought to contribute in the development of drug resistance as tubulin isotypes show differential binding affinities for various anti-cancer agents. Tubulin isotypes ??II, ??III and ??IV show differential binding affinity for colchicine. However, the origin of differential binding affinity is not well understood at the molecular level. Here, we investigate the origin of differential binding affinity of a colchicine analogue N-deacetyl-N-(2-mercaptoacetyl)-colchicine (DAMA-colchicine) for human ??II, ??III and ??IV isotypes, employing sequence analysis, homology modeling, molecular docking, molecular dynamics simulation and MM-GBSA binding free energy calculations. The sequence analysis study shows that the residue compositions are different in the colchicine binding pocket of ??II and ??III, whereas no such difference is present in ??IV tubulin isotypes. Further, the molecular docking and molecular dynamics simulations results show that residue differences present at the colchicine binding pocket weaken the bonding interactions and the correct binding of DAMA-colchicine at the interface of ??II and ??III tubulin isotypes. Post molecular dynamics simulation analysis suggests that these residue variations affect the structure and dynamics of ??II and ??III tubulin isotypes, which in turn affect the binding of DAMA-colchicine. Further, the binding free-energy calculation shows that ??IV tubulin isotype has the highest binding free-energy and ??III has the lowest binding free-energy for DAMA-colchicine. The order of binding free-energy for DAMA-colchicine is ??IV ? ??II >> ??III. Thus, our computational approaches provide an insight into the effect of residue variations on differential binding of ??II, ??III and ??IV tubulin isotypes with DAMA-colchicine and may help to design new analogues with higher binding affinities for tubulin isotypes.

Dataset Information

Probing the origin of tubulin rigidity with molecular simulations.

Publications

Probing the origin of tubulin rigidity with molecular simulations.

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