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PLoS Comput Biol. 2014 Feb 6;10(2):e1003464. doi: 10.1371/journal.pcbi.1003464. eCollection 2014 Feb.

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

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.
2
Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California, United States of America.
3
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America.
4
Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.
5
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America ; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States of America.

Abstract

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.

PMID:
24516374
PMCID:
PMC3916224
DOI:
10.1371/journal.pcbi.1003464
[Indexed for MEDLINE]
Free PMC Article

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