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

Matías A. Zúñiga, Joel B. Alderete, Gonzalo A. Jaña, Pedro A. Fernandez, Maria J. Ramos, Verónica A. Jiménez

Resultado de la investigación: Article

1 Cita (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)1042-1055
Número de páginas14
PublicaciónChemical Biology and Drug Design
Volumen91
N.º5
DOI
EstadoAccepted/In press - 1 ene 2018

Huella dactilar

Molecular modeling
Excipients
Microtubules
Modulation
Association reactions
Tubulin
Ligands
Mutagenesis
Molecular Dynamics Simulation
Principal Component Analysis
Alanine
Principal component analysis
Molecular dynamics
Stabilization
Scanning
Antimitotic Agents
Dimers
Modulators
Free energy
laulimalide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Citar esto

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title = "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.",
keywords = "Mechanism-based drug design, Microtubule stabilizing agents, Molecular modeling, Protein-protein interactions",
author = "Z{\'u}{\~n}iga, {Mat{\'i}as A.} and Alderete, {Joel B.} and Ja{\~n}a, {Gonzalo A.} and Fernandez, {Pedro A.} and Ramos, {Maria J.} and Jim{\'e}nez, {Ver{\'o}nica A.}",
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TY - JOUR

T1 - Modulation of lateral and longitudinal interdimeric interactions in microtubule models by Laulimalide and Peloruside A association

T2 - A molecular modeling approach on the mechanism of microtubule stabilizing agents

AU - Zúñiga, Matías A.

AU - Alderete, Joel B.

AU - Jaña, Gonzalo A.

AU - Fernandez, Pedro A.

AU - Ramos, Maria J.

AU - Jiménez, Verónica A.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Mechanism-based drug design

KW - Microtubule stabilizing agents

KW - Molecular modeling

KW - Protein-protein interactions

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U2 - 10.1111/cbdd.13168

DO - 10.1111/cbdd.13168

M3 - Article

VL - 91

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EP - 1055

JO - Chemical Biology and Drug Design

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