Interdimeric Curvature in Tubulin-Tubulin Complexes Delineates the Microtubule-Destabilizing Properties of Plocabulin.

Journal of Chemical Information and Modeling
Karen R Navarrete, Verónica A Jiménez

Abstract

Plocabulin is a novel microtubule (MT) destabilizer agent with potent antineoplastic activity. This compound binds to the maytansine site at the longitudinal interface between tubulin dimers and exerts a hinge-like effect that disrupts normal microtubule assembly. Plocabulin has emerged as a valuable model for the rational design of novel MT destabilizers because of its unique structural and mechanistic features. To make progress on this matter, detailed molecular-level understanding of the ligand-protein interactions responsible for plocabulin association and the conformation and energetic effects arising from plocabulin binding on the longitudinal interaction between tubulin dimers must be provided. In this work, fully atomistic MD simulations and MM/GBSA binding free-energy calculations were used to examine the association of plocabulin to one or two tubulin dimers in longitudinal arrangement. Our results revealed that plocabulin binding is favored by the addition of a second tubulin dimer and that this ligand promotes the assembly of curved tetrameric arrangements with strengthened longitudinal interdimeric interactions compared to ligand-free systems. The applicability of these findings to the rational discovery of novel M...Continue Reading

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