Modulation of lateral and longitudinal interdimeric interactions in microtubule models by Laulimalide and Peloruside A association. A molecular modeling approach on the mechanism of microtubule stabilizing agents

Abstract

Laulimalide (LAU) and Peloruside A (PLA) are non-taxane microtubule stabilizing agents with promising antimitotic properties. These ligands promote the assembly of microtubules (MTs) by targeting a unique binding site on β-tubulin. The X-ray structure for LAU/PLA-tubulin association was recently elucidated but little information is available regarding the role of these ligands as modulators of interdimeric interactions across MTs. Herein we report the use of Molecular Dynamics (MD), Principal Component Analysis (PCA), MM/GBSA binding free energy calculations, and computational Alanine Scanning Mutagenesis (ASM) to examine effect of LAU/PLA association on lateral and longitudinal contacts between tubulin dimers in reduced MT models. MD and PCA results revealed that LAU/PLA exerts a strong restriction of lateral and longitudinal interdimeric motions, thus enabling the stabilization of the MT lattice. Besides structural effects, LAU/PLA induces a substantial strengthening of longitudinal interdimeric interactions, whereas lateral contacts are less affected by these ligands, as revealed by MM/GBSA and ASM calculations. These results are valuable to increase understanding about the molecular features involved in MT stabilization by LAU/PLA, and to design novel compounds capable of emulating the mode of action of these ligands.

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MD simulations revealed that Laulimalide and Peloruside A association induce a strong restriction in the lateral and longitudinal interdimeric motion between tubulin dimers in reduced microtubule models, which can be related to the stabilization of the microtubule lattice. According to MM/GBSA calculations, Laulimalide and Peloruside A strengthen the longitudinal interdimeric association, whereas lateral interactions are less affected by these ligands.

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