Taxol Allosterically Alters the Dynamics of the Tubulin Dimer and Increases the Flexibility of Microtubules

Mitra, Arpita; Sept, David

doi:10.1529/biophysj.108.133884

Cited by 105 publications

(115 citation statements)

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“…Based on a molecular dynamics simulation of a small section of six tubulin monomers [13], we show that the observed fluctuations of this section are consistent with linear elastic constants for both bending and stretching along the microtubule axis.…”

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confidence: 60%

“…Most often mechanical properties are elucidated in experiments by calculating a forcedisplacement curve as the system is subjected to an applied force. Our simulations were performed as equilibrium molecular dynamics simulations [13] and did not include such a force; however, we can make use of the equipartition theorem and knowledge of the energy involved in the bending, compression or shear of a sheet, assuming a harmonic dependence. In the case of bending, the elastic energy can be described by the bending rigidity of an elastic shell formed by the protofilaments, according to…”

Section: H Y S I C a L R E V I E W L E T T E R S Week Ending 8 Januarmentioning

confidence: 99%

“…An 8 Å structure of the microtubule was solved in subsequent work, and the combination of these two pieces resulted in a molecular level model of microtubule [15]. Using this structure, we performed all-atom molecular dynamics simulations on a fragment of a microtubule with and without Taxol [13]. These were explicit solvent simulations performed using a six monomer portion of two neighboring protofilaments (Fig.…”

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confidence: 99%

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Microtubule Elasticity: Connecting All-Atom Simulations with Continuum Mechanics

Sept

MacKintosh

2010

Phys. Rev. Lett.

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The mechanical properties of microtubules have been extensively studied using a wide range of biophysical techniques, seeking to understand the mechanics of these cylindrical polymers. Here we develop a method for connecting all-atom molecular dynamics simulations with continuum mechanics and show how this can be applied to understand microtubule mechanics. Our coarse-graining technique applied to the microscopic simulation system yields consistent predictions for the Young's modulus and persistence length of microtubules, while clearly demonstrating how binding of the drug Taxol decreases the stiffness of microtubules. The techniques we develop should be widely applicable to other macromolecular systems. DOI: 10.1103/PhysRevLett.104.018101 PACS numbers: 87.16.Ka, 83.10.Ày, 87.15.AÀ, 87.15.La Microtubules are essential players in a wide range of cellular functions. The protein tubulin polymerizes to form these filaments resulting in a hollow cylinder with a diameter of about 25 nm and lengths that range from tens of nanometers to tens of microns. Microtubules are the most rigid structures within the cell and their mechanical stability is particularly important for the role that microtubules play in cell division, cellular transport, and their basic ability to help provide cell shape. The mechanical properties of purified microtubules have been studied extensively using many biophysical techniques, including atomic force microscopy, thermal bending, and single molecule techniques [1][2][3][4][5][6][7][8][9][10][11]. Since microtubules are dynamic polymers and have intrinsic instability, many of these experimental studies have been performed on Taxol-stabilized microtubules, although the mechanical consequences of the drug Taxol for microtubule mechanics remains unclear. The majority of studies have found that the addition of Taxol results in ''softer'' microtubules with a shorter persistence length and lower Young's modulus [1][2][3][4][5], while one published study had found the opposite result [6]. Recently, even the standard elastic model of microtubules characterized by a single elastic bending constant has been called into question by reports of length-dependent stiffness [12]. Thus, in spite of decades of experimental study, many basic questions and puzzles remain concerning the mechanics of even individual microtubules in vitro, let alone in vivo.Here, we combine all-atom simulations and continuum elastic modeling in order to determine both the elastic parameters of persistence length and Young's modulus, as well as to test the applicability of simple, continuum shell elasticity for microtubules. Based on a molecular dynamics simulation of a small section of six tubulin monomers [13], we show that the observed fluctuations of this section are consistent with linear elastic constants for both bending and stretching along the microtubule axis.From these measurements, we determine the effective elastic properties for the microtubule wall, treated as an elastic sheet. With the addition of Taxol, we find in...

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Section: H Y S I C a L R E V I E W L E T T E R S Week Ending 8 Januarmentioning

confidence: 99%

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confidence: 99%

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Microtubule Elasticity: Connecting All-Atom Simulations with Continuum Mechanics

Sept

MacKintosh

2010

Phys. Rev. Lett.

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“…Molecular dynamics simulations on tubulin hexamer were used to study the effects of taxol, a natural microtubule-stabilizing agent. It was suggested that taxol increases b-tubulin flexibility at regions that surround the bound nucleotide and allows the microtubule to counteract the conformational changes induced by nucleotide hydrolysis [30]. More recently, molecular dynamics simulations performed on linear ab-tubulin hexamers brought new arguments to the ''lattice model''.…”

Section: Introductionmentioning

confidence: 99%

The state of the guanosine nucleotide allosterically affects the interfaces of tubulin in protofilament

André

Clément

Adjadj

et al. 2012

J Comput Aided Mol Des

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The dynamics of microtubules is essential for many microtubule-dependent cellular functions such as the mitosis. It has been recognized for a long time that GTP hydrolysis in αβ-tubulin polymers plays a critical role in this dynamics. However, the effects of the changes in the nature of the guanosine nucleotide at the E-site in β-tubulin on microtubule structure and stability are still not well understood. In the present work, we performed all-atom molecular dynamics simulations of a αβα-tubulin heterotrimer harboring a guanosine nucleotide in three different states at the E-site: GTP, GDP-Pi and GDP. We found that changes in the nucleotide state is associated with significant conformational variations at the α-tubulin N- and β-tubulin M-loops which impact the interactions between tubulin protofilaments. The results also show that GTP hydrolysis reduces αβ-tubulin interdimer contacts in favor of intradimer interface. From an atomistic point view, we propose a role for α-tubulin glutamate residue 254 in catalytic magnesium coordination and identified a water molecule in the nucleotide binding pocket which is most probably required for nucleotide hydrolysis. Finally, the results are discussed with reference to the role of taxol in microtubule stability and the recent tubulin-sT2R crystal structures.

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“…For this analysis we applied the protocol described in the work by Mitra et al 29 We first determined the number of independent conformations in our MD trajectories by calculating the autocorrelation function of Root Mean Square Deviation (RMSD) of the structures. We found a correlation time of 2.5 ns, corresponding to 10 independent structures in each of our 25 ns trajectories.…”

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confidence: 99%

In silico study of VP35 inhibitors: from computational alanine scanning to essential dynamics

Dapiaggi

Pieraccini

2015

Mol. BioSyst.

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In recent years the Ebola virus has spread through several countries in Africa, highlighting the need to develop new treatments for this disease and boosting a new research effort on this subject. The Ebola virus Viral Protein 35 (VP35) carries out multiple functions necessary for virus replication and infection, in particular interfering with (IFN)-a/b signaling. Recently, VP35 has been crystallized in complex with small organic molecules able to inhibit its interaction with viral nucleoproteins, thus reducing Ebola infections of cultured cells. In this work, starting from these structures, we carry out a computational study aimed at investigating the energetic and dynamical aspects of the interaction between VP35 and its ligands at the atomic level. Molecular dynamics simulations, computational alanine scanning, root mean square fluctuations bootstrap analysis and essential dynamics analysis were performed. Our results expand the experimental ones obtained in previous works, adding information about the interactions landscape with the identification of a set of new hot-spots residues exerting a critical function in the protein-ligand interaction. Moreover we characterized the dynamics of the complexes, showing that the presence of ligands modifies the overall protein dynamics as well as the behavior of particular protein segments.

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Taxol Allosterically Alters the Dynamics of the Tubulin Dimer and Increases the Flexibility of Microtubules

Cited by 105 publications

References 41 publications

Microtubule Elasticity: Connecting All-Atom Simulations with Continuum Mechanics

Microtubule Elasticity: Connecting All-Atom Simulations with Continuum Mechanics

The state of the guanosine nucleotide allosterically affects the interfaces of tubulin in protofilament

In silico study of VP35 inhibitors: from computational alanine scanning to essential dynamics

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