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

Laulimalide ( LAU ) and Peloruside A ( PLA ) are non‐taxane microtubule stabilizing agents with promising antimitotic properties. These ligands promote the assembly of microtubules ( MT s) 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 MT s. 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.