%0 Journal Article
%T The Free Energy Profile of Tubulin Straight-Bent Conformational Changes, with Implications for Microtubule Assembly and Drug Discovery
%A David A. Agard
%A Lili X. Peng
%A Massimiliano Bonomi
%A Matthew P. Jacobson
%A Monica T. Hsu
%J -
%D 2014
%R 10.1371/journal.pcbi.1003464
%X ¦Á¦Â-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 ¦Á¦Â-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¡ã 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 ¦Á¦Â-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 ¦Á¦Â-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
%K Tubulins
%K Free energy
%K Colchicine
%K Crystal structure
%K Microtubules
%K Molecular dynamics
%K Molecular structure
%K Dimers (Chemical physics)
%U https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003464