The thermodynamics of vinca alkaloid-induced tubulin spirals formation.
Vinca alkaloids are antimitotic, anticancer agents that induce tubulin to form spiral polymers at physiological protein concentrations. We used sedimentation velocity to investigate the effects of six vinca alkaloids on tubulin spiraling. Fitting to a Wyman linkage model reveals a drug dependent change of over two orders of magnitude in spiraling potential, K(1)K(2). Thermodynamic analysis of LnK(1)K(2) data demonstrates large and positive DeltaS values, indicating that tubulin spiral formation is entropically-driven. From the curvature in van't Hoff plots of vinblastine data, we estimate DeltaC(p) for GTP and GDP conditions to be -439 and -396 cal/mol K. Partitioning of DeltaS into the hydrophobic effect, DeltaS(HE), change in rotational/translational freedom, DeltaS(RT) and change in protein conformation, DeltaS(other), demonstrates that the major driving force for tubulin spiral formation is burial of hydrophobic surfaces and that protein conformational changes do not make a significant contribution. Spiraling potential is an indicator of antimitotic activity in vivo, although turbidity studies indicate that there is no correlation between spiraling potential and microtubule inhibition in vitro. Mechanisms that explain this discrepancy are discussed.
Lobert
Sharon
S
School of Nursing, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Ingram
Jeffrey W
JW
Correia
John J
JJ
D019277:Entropy; D011108:Polymers / Q000737:chemistry; D011487:Protein Conformation; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry* / Q000187:drug effects*; D014748:Vinca Alkaloids / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity
D011108:Polymers; D014404:Tubulin; D014748:Vinca Alkaloids