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Quantum effects in the understanding of consciousness.

J Integr Neurosci. 2014 Jun;13(2):229-52

Authors: Hameroff SR, Craddock TJ, Tuszynski JA

Abstract
This paper presents a historical perspective on the development and application of quantum physics methodology beyond physics, especially in biology and in the area of consciousness studies. Quantum physics provides a conceptual framework for the structural aspects of biological systems and processes via quantum chemistry. In recent years individual biological phenomena such as photosynthesis and bird navigation have been experimentally and theoretically analyzed using quantum methods building conceptual foundations for quantum biology. Since consciousness is attributed to human (and possibly animal) mind, quantum underpinnings of cognitive processes are a logical extension. Several proposals, especially the Orch OR hypothesis, have been put forth in an effort to introduce a scientific basis to the theory of consciousness. At the center of these approaches are microtubules as the substrate on which conscious processes in terms of quantum coherence and entanglement can be built. Additionally, Quantum Metabolism, quantum processes in ion channels and quantum effects in sensory stimulation are discussed in this connection. We discuss the challenges and merits related to quantum consciousness approaches as well as their potential extensions.

PMID: 25012711 [PubMed - indexed for MEDLINE]

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Keeping time: could quantum beating in microtubules be the basis for the neural synchrony related to consciousness?

J Integr Neurosci. 2014 Jun;13(2):293-311

Authors: Craddock TJ, Priel A, Tuszynski JA

Abstract
This paper discusses the possibility of quantum coherent oscillations playing a role in neuronal signaling. Consciousness correlates strongly with coherent neural oscillations, however the mechanisms by which neurons synchronize are not fully elucidated. Recent experimental evidence of quantum beats in light-harvesting complexes of plants (LHCII) and bacteria provided a stimulus for seeking similar effects in important structures found in animal cells, especially in neurons. We argue that microtubules (MTs), which play critical roles in all eukaryotic cells, possess structural and functional characteristics that are consistent with quantum coherent excitations in the aromatic groups of their tryptophan residues. Furthermore we outline the consequences of these findings on neuronal processes including the emergence of consciousness.

PMID: 25012713 [PubMed - indexed for MEDLINE]

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A simple method for finding a protein's ligand-binding pockets.

BMC Struct Biol. 2014 Jul 19;14:18

Authors: Saberi Fathi SM, Tuszynski JA

Abstract
BACKGROUND: This paper provides a simple and rapid method for a protein-clustering strategy. The basic idea implemented here is to use computational geometry methods to predict and characterize ligand-binding pockets of a given protein structure. In addition to geometrical characteristics of the protein structure, we consider some simple biochemical properties that help recognize the best candidates for pockets in a protein's active site.
RESULTS: Our results are shown to produce good agreement with known empirical results.
CONCLUSIONS: The method presented in this paper is a low-cost rapid computational method that could be used to classify proteins and other biomolecules, and furthermore could be useful in reducing the cost and time of drug discovery.

PMID: 25038637 [PubMed - indexed for MEDLINE]

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In silico studies and fluorescence binding assays of potential anti-prion compounds reveal an important binding site for prion inhibition from PrP(C) to PrP(Sc).

Eur J Med Chem. 2015 Feb 16;91:118-31

Authors: Pagadala NS, Perez-Pineiro R, Wishart DS, Tuszynski JA

Abstract
To understand the pharmacophore properties of 2-aminothiazoles and design novel inhibitors against the prion protein, a highly predictive 3D quantitative structure-activity relationship (QSAR) has been developed by performing comparative molecular field analysis (CoMFA) and comparative similarity analysis (CoMSIA). Both CoMFA and CoMSIA maps reveal the presence of the oxymethyl groups in meta and para positions on the phenyl ring of compound 17 (N-[4-(3,4-dimethoxyphenyl)-1,3-thiazol-2-yl]quinolin-2-amine), is necessary for activity while electro-negative nitrogen of quinoline is highly favorable to enhance activity. The blind docking results for these compounds show that the compound with quinoline binds with higher affinity than isoquinoline and naphthalene groups. Out of 150 novel compounds retrieved using finger print analysis by pharmacophoric model predicted based on five test sets of compounds, five compounds with diverse scaffolds were selected for biological evaluation as possible PrP inhibitors. Molecular docking combined with fluorescence quenching studies show that these compounds bind to pocket-D of SHaPrP near Trp145. The new antiprion compounds 3 and 6, which bind with the interaction energies of -12.1 and -13.2 kcal/mol, respectively, show fluorescence quenching with binding constant (Kd) values of 15.5 and 44.14 μM, respectively. Further fluorescence binding assays with compound 5, which is similar to 2-aminothiazole as a positive control, also show that the molecule binds to the pocket-D with the binding constant (Kd) value of 84.7 μM. Finally, both molecular docking and a fluorescence binding assay of noscapine as a negative control reveals the same binding site on the surface of pocket-A near a rigid loop between β2 and α2 interacting with Arg164. This high level of correlation between molecular docking and fluorescence quenching studies confirm that these five compounds are likely to act as inhibitors for prion propagation while noscapine might act as a prion accelerator from PrP(C) to PrP(Sc).

PMID: 25042003 [PubMed - indexed for MEDLINE]

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Geometrical comparison of two protein structures using Wigner-D functions.

Proteins. 2014 Oct;82(10):2756-69

Authors: Saberi Fathi SM, White DT, Tuszynski JA

Abstract
In this article, we develop a quantitative comparison method for two arbitrary protein structures. This method uses a root-mean-square deviation characterization and employs a series expansion of the protein's shape function in terms of the Wigner-D functions to define a new criterion, which is called a "similarity value." We further demonstrate that the expansion coefficients for the shape function obtained with the help of the Wigner-D functions correspond to structure factors. Our method addresses the common problem of comparing two proteins with different numbers of atoms. We illustrate it with a worked example.

PMID: 25043646 [PubMed - indexed for MEDLINE]

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Analysis of the strength of interfacial hydrogen bonds between tubulin dimers using quantum theory of atoms in molecules.

Biophys J. 2014 Aug 05;107(3):740-750

Authors: Ayoub AT, Craddock TJA, Klobukowski M, Tuszynski J

Abstract
Microtubules are key structural elements that, among numerous biological functions, maintain the cytoskeleton of the cell and have a major role in cell division, which makes them important cancer chemotherapy targets. Understanding the energy balance that brings tubulin dimers, the building blocks of microtubules, together to form a microtubule is especially important for revealing the mechanism of their dynamic instability. Several studies have been conducted to estimate various contributions to the free energy of microtubule formation. However, the hydrogen-bond contribution was not studied before as a separate component. In this work, we use concepts such as the quantum theory of atoms in molecules to estimate the per-residue strength of hydrogen bonds contributing to the overall stability that brings subunits together in pair of tubulin heterodimers, across both the longitudinal and lateral interfaces. Our study shows that hydrogen bonding plays a major role in the stability of tubulin systems. Several residues that are crucial to the binding of vinca alkaloids are shown to be strongly involved in longitudinal microtubule stabilization. This indicates a direct relation between the binding of these agents and the effect on the interfacial hydrogen-bonding network, and explains the mechanism of their action. Lateral contacts showed much higher stability than longitudinal ones (-462 ± 70 vs. -392 ± 59 kJ/mol), which suggests a dramatic lateral stabilization effect of the GTP cap in the β-subunit. The role of the M-loop in lateral stability in absence of taxol was shown to be minor. The B-lattice lateral hydrogen bonds are shown to be comparable in strength to the A-lattice ones (-462 ± 70 vs. -472 ± 46 kJ/mol). These findings establish the importance of hydrogen bonds to the stability of tubulin systems.

PMID: 25099813 [PubMed - indexed for MEDLINE]

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A human ether-á-go-go-related (hERG) ion channel atomistic model generated by long supercomputer molecular dynamics simulations and its use in predicting drug cardiotoxicity.

Toxicol Lett. 2014 Nov 04;230(3):382-92

Authors: Anwar-Mohamed A, Barakat KH, Bhat R, Noskov SY, Tyrrell DL, Tuszynski JA, Houghton M

Abstract
Acquired cardiac long QT syndrome (LQTS) is a frequent drug-induced toxic event that is often caused through blocking of the human ether-á-go-go-related (hERG) K(+) ion channel. This has led to the removal of several major drugs post-approval and is a frequent cause of termination of clinical trials. We report here a computational atomistic model derived using long molecular dynamics that allows sensitive prediction of hERG blockage. It identified drug-mediated hERG blocking activity of a test panel of 18 compounds with high sensitivity and specificity and was experimentally validated using hERG binding assays and patch clamp electrophysiological assays. The model discriminates between potent, weak, and non-hERG blockers and is superior to previous computational methods. This computational model serves as a powerful new tool to predict hERG blocking thus rendering drug development safer and more efficient. As an example, we show that a drug that was halted recently in clinical development because of severe cardiotoxicity is a potent inhibitor of hERG in two different biological assays which could have been predicted using our new computational model.

PMID: 25127758 [PubMed - indexed for MEDLINE]

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The feasibility of coherent energy transfer in microtubules.

J R Soc Interface. 2014 Nov 06;11(100):20140677

Authors: Craddock TJ, Friesen D, Mane J, Hameroff S, Tuszynski JA

Abstract
It was once purported that biological systems were far too 'warm and wet' to support quantum phenomena mainly owing to thermal effects disrupting quantum coherence. However, recent experimental results and theoretical analyses have shown that thermal energy may assist, rather than disrupt, quantum coherent transport, especially in the 'dry' hydrophobic interiors of biomolecules. Specifically, evidence has been accumulating for the necessary involvement of quantum coherent energy transfer between uniquely arranged chromophores in light harvesting photosynthetic complexes. The 'tubulin' subunit proteins, which comprise microtubules, also possess a distinct architecture of chromophores, namely aromatic amino acids, including tryptophan. The geometry and dipolar properties of these aromatics are similar to those found in photosynthetic units indicating that tubulin may support coherent energy transfer. Tubulin aggregated into microtubule geometric lattices may support such energy transfer, which could be important for biological signalling and communication essential to living processes. Here, we perform a computational investigation of energy transfer between chromophoric amino acids in tubulin via dipole excitations coupled to the surrounding thermal environment. We present the spatial structure and energetic properties of the tryptophan residues in the microtubule constituent protein tubulin. Plausibility arguments for the conditions favouring a quantum mechanism of signal propagation along a microtubule are provided. Overall, we find that coherent energy transfer in tubulin and microtubules is biologically feasible.

PMID: 25232047 [PubMed - indexed for MEDLINE]

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Investigation of the Josephin Domain protein-protein interaction by molecular dynamics.

PLoS One. 2014;9(9):e108677

Authors: Deriu MA, Grasso G, Licandro G, Danani A, Gallo D, Tuszynski JA, Morbiducci U

Abstract
Spinocerebellar ataxia (SCA) 3, the most common form of SCA, is a neurodegenerative rare disease characterized by polyglutamine tract expansion and self-assembly of Ataxin3 (At3) misfolded proteins into highly organized fibrillar aggregates. The At3 N-terminal Josephin Domain (JD) has been suggested as being responsible for mediating the initial phase of the At3 double-step fibrillogenesis. Several issues concerning the residues involved in the JD's aggregation and, more generally, the JD clumping mechanism have not been clarified yet. In this paper we present an investigation focusing on the JD protein-protein interaction by means of molecular modeling. Our results suggest possible aminoacids involved in JD contact together with local and non-local effects following JD dimerization. Surprisingly, JD conformational changes following the binding may involve ubiquitin binding sites and hairpin region even though they do not pertain to the JD interaction surfaces. Moreover, the JD binding event has been found to alter the hairpin open-like conformation toward a closed-like arrangement over the simulated timescale. Finally, our results suggest that the JD aggregation might be a multi-step process, with an initial fast JD-JD binding mainly driven by Arg101, followed by slower structural global rearrangements involving the exposure to the solvent of Leu84-Trp87, which might play a role in a second step of JD aggregation.

PMID: 25268243 [PubMed - indexed for MEDLINE]

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The Unique Binding Mode of Laulimalide to Two Tubulin Protofilaments.

Chem Biol Drug Des. 2015 Aug;86(2):190-9

Authors: Churchill CD, Klobukowski M, Tuszynski JA

Abstract
Laulimalide, a cancer chemotherapeutic in preclinical development, has a unique binding site located on two adjacent β-tubulin units between tubulin protofilaments of a microtubule. Our extended protein model more accurately mimics the microtubule environment, and together with a 135 ns molecular dynamics simulation, identifies a new binding mode for laulimalide, which differs from the modes presented in work using smaller protein models. The new laulimalide-residue interactions that are computationally revealed explain the contacts observed via independent mass shift perturbation experiments. The inclusion of explicit solvent shows that many laulimalide-tubulin interactions are water mediated. The new contacts between the drug and the microtubule structure not only improve our understanding of laulimalide binding but also will be essential for efficient derivatization and optimization of this prospective cancer chemotherapy agent. Observed changes in secondary protein structure implicate the S7-H9 loop (M-loop) and H1'-S2 loop in the mechanism by which laulimalide stabilizes microtubules to exert its cytotoxic effects.

PMID: 25376845 [PubMed - indexed for MEDLINE]

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Ranking the Binding Energies of p53 Mutant Activators and Their ADMET Properties.

Chem Biol Drug Des. 2015 Aug;86(2):163-72

Authors: Omar SI, Tuszynski J

Abstract
The guardian of the genome, p53, is the most mutated protein found in all cancer cells. Restoration of wild-type activity to mutant p53 offers promise to eradicate cancer cells using novel pharmacological agents. Several molecules have already been found to activate mutant p53. While the exact mechanism of action of these compounds has not been fully understood, a transiently open pocket has been identified in some mutants. In our study, we docked twelve known activators to p53 into the open pocket to further understand their mechanism of action and rank the best binders. In addition, we predicted the absorption, distribution, metabolism, excretion and toxicity properties of these compounds to assess their pharmaceutical usefulness. Our studies showed that alkylating ligands do not all bind at the same position, probably due to their varying sizes. In addition, we found that non-alkylating ligands are capable of binding at the same pocket and directly interacting with Cys124. The comparison of the different ligands demonstrates that stictic acid has a great potential as a p53 activator in terms of less adverse effects although it has poorer pharmacokinetic properties.

PMID: 25407396 [PubMed - indexed for MEDLINE]

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Biological wires, communication systems, and implications for disease.

Biosystems. 2015 Jan;127:14-27

Authors: Friesen DE, Craddock TJ, Kalra AP, Tuszynski JA

Abstract
Microtubules, actin, and collagen are macromolecular structures that compose a large percentage of the proteins in the human body, helping form and maintain both intracellular and extracellular structure. They are biological wires and are structurally connected through various other proteins. Microtubules (MTs) have been theorized to be involved in classical and quantum information processing, and evidence continues to suggest possible semiconduction through MTs. The previous Dendritic Cytoskeleton Information Processing Model has hypothesized how MTs and actin form a communication network in neurons. Here, we review information transfer possibilities involving MTs, actin, and collagen, and the evidence of an organism-wide high-speed communication network that may regulate morphogenesis and cellular proliferation. The direct and indirect evidence in support of this hypothesis, and implications for chronic diseases such as cancer and neurodegenerative diseases are discussed.

PMID: 25448891 [PubMed - indexed for MEDLINE]

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Mathematical and computational modeling in biology at multiple scales.

Theor Biol Med Model. 2014 Dec 27;11:52

Authors: Tuszynski JA, Winter P, White D, Tseng CY, Sahu KK, Gentile F, Spasevska I, Omar SI, Nayebi N, Churchill CD, Klobukowski M, El-Magd RM

Abstract
A variety of topics are reviewed in the area of mathematical and computational modeling in biology, covering the range of scales from populations of organisms to electrons in atoms. The use of maximum entropy as an inference tool in the fields of biology and drug discovery is discussed. Mathematical and computational methods and models in the areas of epidemiology, cell physiology and cancer are surveyed. The technique of molecular dynamics is covered, with special attention to force fields for protein simulations and methods for the calculation of solvation free energies. The utility of quantum mechanical methods in biophysical and biochemical modeling is explored. The field of computational enzymology is examined.

PMID: 25542608 [PubMed - indexed for MEDLINE]

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A computational strategy to select optimized protein targets for drug development toward the control of cancer diseases.

PLoS One. 2015;10(1):e0115054

Authors: Carels N, Tilli T, Tuszynski JA

Abstract
In this report, we describe a strategy for the optimized selection of protein targets suitable for drug development against neoplastic diseases taking the particular case of breast cancer as an example. We combined human interactome and transcriptome data from malignant and control cell lines because highly connected proteins that are up-regulated in malignant cell lines are expected to be suitable protein targets for chemotherapy with a lower rate of undesirable side effects. We normalized transcriptome data and applied a statistic treatment to objectively extract the sub-networks of down- and up-regulated genes whose proteins effectively interact. We chose the most connected ones that act as protein hubs, most being in the signaling network. We show that the protein targets effectively identified by the combination of protein connectivity and differential expression are known as suitable targets for the successful chemotherapy of breast cancer. Interestingly, we found additional proteins, not generally targeted by drug treatments, which might justify the extension of existing formulation by addition of inhibitors designed against these proteins with the consequence of improving therapeutic outcomes. The molecular alterations observed in breast cancer cell lines represent either driver events and/or driver pathways that are necessary for breast cancer development or progression. However, it is clear that signaling mechanisms of the luminal A, B and triple negative subtypes are different. Furthermore, the up- and down-regulated networks predicted subtype-specific drug targets and possible compensation circuits between up- and down-regulated genes. We believe these results may have significant clinical implications in the personalized treatment of cancer patients allowing an objective approach to the recycling of the arsenal of available drugs to the specific case of each breast cancer given their distinct qualitative and quantitative molecular traits.

PMID: 25625699 [PubMed - indexed for MEDLINE]

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Anesthetics act in quantum channels in brain microtubules to prevent consciousness.

Curr Top Med Chem. 2015;15(6):523-33

Authors: Craddock TJ, Hameroff SR, Ayoub AT, Klobukowski M, Tuszynski JA

Abstract
The mechanism by which anesthetic gases selectively prevent consciousness and memory (sparing non-conscious brain functions) remains unknown. At the turn of the 20(th) century Meyer and Overton showed that potency of structurally dissimilar anesthetic gas molecules correlated precisely over many orders of magnitude with one factor, solubility in a non-polar, 'hydrophobic' medium akin to olive oil. In the 1980s Franks and Lieb showed anesthetics acted in such a medium within proteins, suggesting post-synaptic membrane receptors. But anesthetic studies on such proteins yielded only confusing results. In recent years Eckenhoff and colleagues have found anesthetic action in microtubules, cytoskeletal polymers of the protein tubulin inside brain neurons. 'Quantum mobility' in microtubules has been proposed to mediate consciousness. Through molecular modeling we have previously shown: (1) olive oil-like non-polar, hydrophobic quantum mobility pathways ('quantum channels') of tryptophan rings in tubulin, (2) binding of anesthetic gas molecules in these channels, and (3) capabilities for π-electron resonant energy transfer, or exciton hopping, among tryptophan aromatic rings in quantum channels, similar to photosynthesis protein quantum coherence. Here, we show anesthetic molecules can impair π-resonance energy transfer and exciton hopping in tubulin quantum channels, and thus account for selective action of anesthetics on consciousness and memory.

PMID: 25714379 [PubMed - indexed for MEDLINE]

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On the classical vibrational coherence of carbonyl groups in the selectivity filter backbone of the KcsA ion channel.

J Integr Neurosci. 2015 Jun;14(2):195-206

Authors: Salari V, Sajadi M, Bassereh H, Rezania V, Alaei M, Tuszynski JA

Abstract
It has been suggested that quantum coherence in the selectivity filter of ion channel may play a key role in fast conduction and selectivity of ions. However, it has not been clearly elucidated yet why classical coherence is not sufficient for this purpose. In this paper, we investigate the classical vibrational coherence between carbonyl groups oscillations in the selectivity filter of KcsA ion channels based on the data obtained from molecular dynamics simulations. Our results show that classical coherence plays no effective role in fast ionic conduction.

PMID: 25990939 [PubMed - indexed for MEDLINE]

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Structure Based Modeling of Small Molecules Binding to the TLR7 by Atomistic Level Simulations.

Molecules. 2015 May 08;20(5):8316-40

Authors: Gentile F, Deriu MA, Licandro G, Prunotto A, Danani A, Tuszynski JA

Abstract
Toll-Like Receptors (TLR) are a large family of proteins involved in the immune system response. Both the activation and the inhibition of these receptors can have positive effects on several diseases, including viral pathologies and cancer, therefore prompting the development of new compounds. In order to provide new indications for the design of Toll-Like Receptor 7 (TLR7)-targeting drugs, the mechanism of interaction between the TLR7 and two important classes of agonists (imidazoquinoline and adenine derivatives) was investigated through docking and Molecular Dynamics simulations. To perform the computational analysis, a new model for the dimeric form of the receptors was necessary and therefore created. Qualitative and quantitative differences between agonists and inactive compounds were determined. The in silico results were compared with previous experimental observations and employed to define the ligand binding mechanism of TLR7.

PMID: 26007168 [PubMed - indexed for MEDLINE]

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Design principles for cancer therapy guided by changes in complexity of protein-protein interaction networks.

Biol Direct. 2015 May 28;10:32

Authors: Benzekry S, Tuszynski JA, Rietman EA, Lakka Klement G

Abstract
BACKGROUND: The ever-increasing expanse of online bioinformatics data is enabling new ways to, not only explore the visualization of these data, but also to apply novel mathematical methods to extract meaningful information for clinically relevant analysis of pathways and treatment decisions. One of the methods used for computing topological characteristics of a space at different spatial resolutions is persistent homology. This concept can also be applied to network theory, and more specifically to protein-protein interaction networks, where the number of rings in an individual cancer network represents a measure of complexity.
RESULTS: We observed a linear correlation of R = -0.55 between persistent homology and 5-year survival of patients with a variety of cancers. This relationship was used to predict the proteins within a protein-protein interaction network with the most impact on cancer progression. By re-computing the persistent homology after computationally removing an individual node (protein) from the protein-protein interaction network, we were able to evaluate whether such an inhibition would lead to improvement in patient survival. The power of this approach lied in its ability to identify the effects of inhibition of multiple proteins and in the ability to expose whether the effect of a single inhibition may be amplified by inhibition of other proteins. More importantly, we illustrate specific examples of persistent homology calculations, which correctly predict the survival benefit observed effects in clinical trials using inhibitors of the identified molecular target.
CONCLUSIONS: We propose that computational approaches such as persistent homology may be used in the future for selection of molecular therapies in clinic. The technique uses a mathematical algorithm to evaluate the node (protein) whose inhibition has the highest potential to reduce network complexity. The greater the drop in persistent homology, the greater reduction in network complexity, and thus a larger potential for survival benefit. We hope that the use of advanced mathematics in medicine will provide timely information about the best drug combination for patients, and avoid the expense associated with an unsuccessful clinical trial, where drug(s) did not show a survival benefit.

PMID: 26018239 [PubMed - indexed for MEDLINE]

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Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly.

PLoS Comput Biol. 2015 Jun;11(6):e1004313

Authors: Ayoub AT, Klobukowski M, Tuszynski JA

Abstract
Microtubules are long filamentous hollow cylinders whose surfaces form lattice structures of αβ-tubulin heterodimers. They perform multiple physiological roles in eukaryotic cells and are targets for therapeutic interventions. In our study, we carried out all-atom molecular dynamics simulations for arbitrarily long microtubules that have either GDP or GTP molecules in the E-site of β-tubulin. A detailed energy balance of the MM/GBSA inter-dimer interaction energy per residue contributing to the overall lateral and longitudinal structural stability was performed. The obtained results identified the key residues and tubulin domains according to their energetic contributions. They also identified the molecular forces that drive microtubule disassembly. At the tip of the plus end of the microtubule, the uneven distribution of longitudinal interaction energies within a protofilament generates a torque that bends tubulin outwardly with respect to the cylinder's axis causing disassembly. In the presence of GTP, this torque is opposed by lateral interactions that prevent outward curling, thus stabilizing the whole microtubule. Once GTP hydrolysis reaches the tip of the microtubule (lateral cap), lateral interactions become much weaker, allowing tubulin dimers to bend outwards, causing disassembly. The role of magnesium in the process of outward curling has also been demonstrated. This study also showed that the microtubule seam is the most energetically labile inter-dimer interface and could serve as a trigger point for disassembly. Based on a detailed balance of the energetic contributions per amino acid residue in the microtubule, numerous other analyses could be performed to give additional insights into the properties of microtubule dynamic instability.

PMID: 26030285 [PubMed - indexed for MEDLINE]

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Elucidating the mechanism of action of the clinically approved taxanes: a comprehensive comparison of local and allosteric effects.

Chem Biol Drug Des. 2015 Nov;86(5):1253-66

Authors: Churchill CD, Klobukowski M, Tuszynski JA

Abstract
The clinically approved taxanes (paclitaxel, docetaxel and cabazitaxel) target the tubulin protein in microtubules. Despite the clinical success of these agents, the mechanism of action of this class of drugs remains elusive, making rational design of taxanes difficult. Molecular dynamics simulations of these three taxanes with the αβ-tubulin heterodimer examine the similarities and differences in the effects of the drugs on tubulin, probing both local and allosteric effects. Despite their structural similarity, the drugs adopt different conformations in the binding site on β-tubulin. The taxanes similarly increase the helical character of α- and β-tubulins. No correlations are found between microtubule assembly and (i) binding affinity or (ii) the role of the M-loop in enhancing lateral contacts. Instead, changes in intra- and interdimer longitudinal contacts are indicative of the mechanism of action of the taxanes. We find β:H1-S1', and more importantly β:H9 and β:H10, play a role translating the effect of local drug binding in β-tubulin to an allosteric effect in α-tubulin and propose that the displacement of these secondary structures towards α-tubulin may be used as a predictor of the effect of taxanes on the tubulin heterodimers in rational drug design approaches.

PMID: 26032329 [PubMed - indexed for MEDLINE]