The free energy profile of tubulin straight-bent conformational changes, with implications for microtubule assembly and drug discovery.

Autor: Lili X Peng, Monica T Hsu, Massimiliano Bonomi, David A Agard, Matthew P Jacobson
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Zdroj: PLoS Computational Biology, Vol 10, Iss 2, p e1003464 (2014)
Druh dokumentu: article
ISSN: 1553-734X
1553-7358
DOI: 10.1371/journal.pcbi.1003464
Popis: αβ-tubulin dimers need to convert between a 'bent' conformation observed for free dimers in solution and a 'straight' conformation required for incorporation into the microtubule lattice. Here, we investigate the free energy landscape of αβ-tubulin using molecular dynamics simulations, emphasizing implications for models of assembly, and modulation of the conformational landscape by colchicine, a tubulin-binding drug that inhibits microtubule polymerization. Specifically, we performed molecular dynamics, potential-of-mean force simulations to obtain the free energy profile for unpolymerized GDP-bound tubulin as a function of the ∼12° intradimer rotation differentiating the straight and bent conformers. Our results predict that the unassembled GDP-tubulin heterodimer exists in a continuum of conformations ranging between straight and bent, but, in agreement with existing structural data, suggests that an intermediate bent state has a lower free energy (by ∼1 kcal/mol) and thus dominates in solution. In agreement with predictions of the lattice model of microtubule assembly, lateral binding of two αβ-tubulins strongly shifts the conformational equilibrium towards the straight state, which is then ∼1 kcal/mol lower in free energy than the bent state. Finally, calculations of colchicine binding to a single αβ-tubulin dimer strongly shifts the equilibrium toward the bent states, and disfavors the straight state to the extent that it is no longer thermodynamically populated.
Databáze: Directory of Open Access Journals
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