Magnetic Monopole Search with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions Interpreted in Photon-Fusion and Drell-Yan Production.

2 weeks ago
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Magnetic Monopole Search with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions Interpreted in Photon-Fusion and Drell-Yan Production.

Phys Rev Lett. 2019 Jul 12;123(2):021802

Authors: Acharya B, Alexandre J, Baines S, Benes P, Bergmann B, Bernabéu J, Bevan A, Branzas H, Campbell M, Cecchini S, Cho YM, de Montigny M, De Roeck A, Ellis JR, El Sawy M, Fairbairn M, Felea D, Frank M, Hays J, Hirt AM, Janecek J, Kim DW, Korzenev A, Lacarrère DH, Lee SC, Leroy C, Levi G, Lionti A, Mamuzic J, Margiotta A, Mauri N, Mavromatos NE, Mermod P, Mieskolainen M, Millward L, Mitsou VA, Orava R, Ostrovskiy I, Papavassiliou J, Parker B, Patrizii L, Păvălaş GE, Pinfold JL, Popa V, Pozzato M, Pospisil S, Rajantie A, Ruiz de Austri R, Sahnoun Z, Sakellariadou M, Santra A, Sarkar S, Semenoff G, Shaa A, Sirri G, Sliwa K, Soluk R, Spurio M, Staelens M, Suk M, Tenti M, Togo V, Tuszyński JA, Vento V, Vives O, Vykydal Z, Wall A, Zgura IS, MoEDAL Collaboration

Abstract
MoEDAL is designed to identify new physics in the form of stable or pseudostable highly ionizing particles produced in high-energy Large Hadron Collider (LHC) collisions. Here we update our previous search for magnetic monopoles in Run 2 using the full trapping detector with almost four times more material and almost twice more integrated luminosity. For the first time at the LHC, the data were interpreted in terms of photon-fusion monopole direct production in addition to the Drell-Yan-like mechanism. The MoEDAL trapping detector, consisting of 794 kg of aluminum samples installed in the forward and lateral regions, was exposed to 4.0  fb^{-1} of 13 TeV proton-proton collisions at the LHCb interaction point and analyzed by searching for induced persistent currents after passage through a superconducting magnetometer. Magnetic charges equal to or above the Dirac charge are excluded in all samples. Monopole spins 0, ½, and 1 are considered and both velocity-independent and-dependent couplings are assumed. This search provides the best current laboratory constraints for monopoles with magnetic charges ranging from two to five times the Dirac charge.

PMID: 31386510 [PubMed - in process]

Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1-XPF.

2 weeks 5 days ago
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Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1-XPF.

J Med Chem. 2019 Aug 01;:

Authors: Elmenoufy A, Gentile F, Jay D, Karimi-Busheri F, Yang X, Soueidan OM, Weilbeer C, Mani RS, Barakat KH, Tuszynski J, Weinfeld M, West FG

Abstract
The ERCC1-XPF heterodimer is a 5´-3´ structure-specific endonuclease, which plays an essential role in several DNA repair pathways in mammalian cells. ERCC1-XPF is primarily involved in the repair of chemically-induced helix-distorting and bulky DNA lesions, such as cyclobutane pyrimidine dimers (CPDs), and DNA interstrand crosslinks. Inhibition of ERCC1-XPF has been shown to potentiate cytotoxicity of platinum-based drugs and cyclophosphamide in cancer cells. In this study, the previously described ERCC1-XPF inhibitor 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-methylpiperazin-1-yl)methyl)phenol (F06) was used as a reference compound. Following the outcome of docking-based virtual screening (VS), we synthesized seven novel derivatives of F06 that were identified in silico as being likely to have high binding affinity for the ERCC1-XPF heterodimerization interface by interacting with the XPF double helix-hairpin-helix (HhH2) domain. Two of the new compounds, 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-cyclohexylpiperazin-1-yl)methyl)phenol (compound 3) and 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-(2-(dimethylamino)ethyl) piperazin-1-yl) methyl) phenol (compound 4), were shown to be potent inhibitors of ERCC1-XPF activity in vitro. Compound 4 showed a significant inhibition of the removal of CPDs in UV-irradiated cells and the capacity to sensitize colorectal cancer cells to UV radiation and cyclophosphamide.

PMID: 31369707 [PubMed - as supplied by publisher]

Tubulin response to intense nanosecond-scale electric field in molecular dynamics simulation.

4 weeks 2 days ago
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Tubulin response to intense nanosecond-scale electric field in molecular dynamics simulation.

Sci Rep. 2019 Jul 19;9(1):10477

Authors: Marracino P, Havelka D, Průša J, Liberti M, Tuszynski J, Ayoub AT, Apollonio F, Cifra M

Abstract
Intense pulsed electric fields are known to act at the cell membrane level and are already being exploited in biomedical and biotechnological applications. However, it is not clear if electric pulses within biomedically-attainable parameters could directly influence intra-cellular components such as cytoskeletal proteins. If so, a molecular mechanism of action could be uncovered for therapeutic applications of such electric fields. To help clarify this question, we first identified that a tubulin heterodimer is a natural biological target for intense electric fields due to its exceptional electric properties and crucial roles played in cell division. Using molecular dynamics simulations, we then demonstrated that an intense - yet experimentally attainable - electric field of nanosecond duration can affect the bβ-tubulin's C-terminus conformations and also influence local electrostatic properties at the GTPase as well as the binding sites of major tubulin drugs site. Our results suggest that intense nanosecond electric pulses could be used for physical modulation of microtubule dynamics. Since a nanosecond pulsed electric field can penetrate the tissues and cellular membranes due to its broadband spectrum, our results are also potentially significant for the development of new therapeutic protocols.

PMID: 31324834 [PubMed - in process]

How signals of calcium ions initiate the beats of cilia and flagella.

2 months ago
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How signals of calcium ions initiate the beats of cilia and flagella.

Biosystems. 2019 Jun 13;:

Authors: Sataric MV, Nemeš T, Sekulic D, Tuszynski JA

Abstract
Cilia and flagella are cell organelles serving basic roles in cellular motility. Ciliary movement is performed by a sweeping-like repeated bending motion, which gives rise to a self-propagating "ciliary beat". The hallmark structure in cilia is the axoneme, a stable architecture of microtubule doublets. The motion of axoneme is powered by the axonemal dynein motor family powered by ATP hydrolysis. It is still unclear how the organized beat of cilium and flagella emerges from the combined action of hundreds of dynein molecules. It has been hypothesized that such coordination is mediated by mechanical stress due to transverse, radial or sliding deformations. The beating asymmetry is crucial for airway ciliary function and it requires tubulin glutamination a unique posttranslational modification of C-termini of constituent microtubules that is highly abundant in cilia and flagella. The exact role of tubulin glutamination in ciliary or flagellar function is still unclear. In this paper we analyze the role of calcium (Ca2+) ions based on the experimental evidence that the flagellar asymmetry can be increased due to the entry of extracellular Ca2+ through, for example, the nimodipine-sensitive pathway located in the flagella. We propose a new scenario based on the polyelectrolyte properties of cellular microtubules (MTs) such that dynamic influx of Ca2+ ions provides the initiation and synchronization of dynein sliding along microtubules. We also point out the possible interplay between tubulin polyglutaminated C-termini and localized pulses of Ca2+ ions along microtubules.

PMID: 31202860 [PubMed - as supplied by publisher]

Molecular orbitals of delocalized dipole-bound electron clouds in neuronal domains.

2 months ago
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Molecular orbitals of delocalized dipole-bound electron clouds in neuronal domains.

Biosystems. 2019 Jun 10;:103982

Authors: Poznanski RR, Cacha LA, Latif AZA, Salleh SH, Ali J, Yupapin PP, Tuszynski JA, Ariff TM

Abstract
We have further developed the two-brains hypothesis as a form of biological complementarity (or complementary relationship) of endogenously induced weak magnetic fields in the electromagnetic brain. Here, locally induced magnetic field between electron magnetic dipole moments of delocalized electron clouds in neuronal domains are complementary to the exogenous electromagnetic waves created by the oscillating molecular dipole in the electro-ionic brain. In this paper, we mathematically model the integral operation of the electromagnetic grid, especially in regard to the functional role of atomic orbitals of dipole-bound delocalized electrons. A quantum molecular dynamic approach under quantum equilibrium conditions is taken to illustrate phase differences between quasi-free electrons tethered to an oscillating molecular core. We use a simplified version of the many-body problem to analytically solve the macro-quantum wave equation (equivalent to the Kohn-Sham equation) in order to compute the molecular orbital approximated as the mechanical angular momentum due to non-adiabatic motion of the molecular core. We address how the effects of the enveloping fields of dipole-bound delocalized electrons as 'guidance waves' affect delocalized macro-quantum wave functions in generating nonlocal phase correlations. The intrinsic magnetic properties of the origins of the endogenous electromagnetic field are considered a nested hierarchy of electromagnetic fields of brain activity that includes electromagnetic patterns in three-dimensional space. The coupling between the two-brains may involve an 'anticipatory affect' underlying the conceptualization of anticipation as potentiality arising from the macro-quantum potential energy or electrostatic effects of residual charges in the quantum and classical subsystems of the two-brains that occurs through partitioning of the potential energy of the combined quantum molecular dynamic system.

PMID: 31195028 [PubMed - as supplied by publisher]

The Role of Structural Polymorphism in Driving the Mechanical Performance of the Alzheimer's Beta Amyloid Fibrils.

2 months 4 weeks ago
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The Role of Structural Polymorphism in Driving the Mechanical Performance of the Alzheimer's Beta Amyloid Fibrils.

Front Bioeng Biotechnol. 2019;7:83

Authors: Grasso G, Rebella M, Morbiducci U, Tuszynski JA, Danani A, Deriu MA

Abstract
Alzheimer's Disease (AD) is related with the abnormal aggregation of amyloid β-peptides Aβ1-40 and Aβ1-42, the latter having a polymorphic character which gives rise to U- or S-shaped fibrils. Elucidating the role played by the nanoscale-material architecture on the amyloid fibril stability is a crucial breakthrough to better understand the pathological nature of amyloid structures and to support the rational design of bio-inspired materials. The computational study here presented highlights the superior mechanical behavior of the S-architecture, characterized by a Young's modulus markedly higher than the U-shaped architecture. The S-architecture showed a higher mechanical resistance to the enforced deformation along the fibril axis, consequence of a better interchain hydrogen bonds' distribution. In conclusion, this study, focusing the attention on the pivotal multiscale relationship between molecular phenomena and material properties, suggests the S-shaped Aβ1-42 species as a target of election in computational screen/design/optimization of effective aggregation modulators.

PMID: 31106199 [PubMed]

Theorizing how the brain encodes consciousness based on negentropic entanglement.

3 months ago
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Theorizing how the brain encodes consciousness based on negentropic entanglement.

J Integr Neurosci. 2019 Mar 30;18(1):1-10

Authors: Poznanski RR, Cacha LA, Latif AZA, Salleh SH, Ali J, Yupapin P, Tuszynski JA, Tengku MA

Abstract
The physicality of subjectivity is explained through a theoretical conceptualization of guidance waves informing meaning in negentropically entangled non-electrolytic brain regions. Subjectivity manifests its influence at the microscopic scale of matter originating from de Broglie 'hidden' thermodynamics as action of guidance waves. The preconscious experienceability of subjectivity is associated with a nested hierarchy of microprocesses, which are actualized as a continuum of patterns of discrete atomic microfeels (or "qualia"). The mechanism is suggested to be through negentropic entanglement of hierarchical thermodynamic transfer of information as thermo-qubits originating from nonpolarized regions of actin-binding proteinaceous structures of nonsynaptic spines. The resultant continuous stream of intrinsic information entails a negentropic action (or experiential flow of thermo-quantum internal energy that results in a negentropic force) which is encoded through the non-zero real component of the mean approximation of the negentropic force as a 'consciousness code'. Consciousness consisting of two major subprocesses: (1) preconscious experienceability and (2) conscious experience. Both are encapsulated by nonreductive physicalism and panexperiential materialism. The subprocess (1) governing "subjectivity" carries many microprocesses leading to the actualization of discrete atomic microfeels by the 'consciousness code'. These atomic microfeels constitute internal energy that results in the transfer intrinsic information in terms of thermo-qubits. These thermo-qubits are realized as thermal entropy and sensed by subprocess (2) governing "self-awareness" in conscious experience.

PMID: 31091842 [PubMed - in process]

An Overview of Molecular Modeling for Drug Discovery with Specific Illustrative Examples of Applications.

3 months 2 weeks ago
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An Overview of Molecular Modeling for Drug Discovery with Specific Illustrative Examples of Applications.

Molecules. 2019 Apr 30;24(9):

Authors: Aminpour M, Montemagno C, Tuszynski JA

Abstract
In this paper we review the current status of high-performance computing applications in the general area of drug discovery. We provide an introduction to the methodologies applied at atomic and molecular scales, followed by three specific examples of implementation of these tools. The first example describes in silico modeling of the adsorption of small molecules to organic and inorganic surfaces, which may be applied to drug delivery issues. The second example involves DNA translocation through nanopores with major significance to DNA sequencing efforts. The final example offers an overview of computer-aided drug design, with some illustrative examples of its usefulness.

PMID: 31052253 [PubMed - in process]

The molecular mechanism of action of methylene quinuclidinone and its effects on the structure of p53 mutants.

7 months ago
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The molecular mechanism of action of methylene quinuclidinone and its effects on the structure of p53 mutants.

Oncotarget. 2018 Dec 14;9(98):37137-37156

Authors: Omar SI, Tuszynski J

Abstract
One of the most important tumor suppressor proteins in eukaryotic cells is the transcription factor called p53. The importance of this protein in cells comes from the fact that it regulates a wide variety of cellular processes including the cell cycle, metabolism, DNA repair, senescence and apoptosis. In cancer cells, p53 is a major target as the most mutated protein, which has led to the search for potential activators of the mutant protein. Currently, the only mutated-p53 activator in clinical trials is a small molecule called APR-246. There is evidence that the active metabolite of APR-246 binds covalently to mutant p53 and restores its wild-type (wt) activity. In this work, we created atomistic in silico models of the wt, mutant and drugged mutant p53 proteins each in complex with DNA. Using molecular dynamics simulations we generated equilibrated models of the complexes. Detailed analysis revealed that the binding of the APR-246 active metabolite to the mutant proteins alters their interaction with DNA. In particular, the binding of the molecule at loop L1 of the protein allows the loop to anchor the protein to DNA similarly to wt p53. Several important p53-DNA interactions lost due to mutation were also restored in the drugged mutants. These findings, not only provide a possible mechanism of action of this drug, but also criteria to use in virtual screening campaigns for other p53 activators.

PMID: 30647850 [PubMed]

EDEn-Electroceutical Design Environment: Ion Channel Tissue Expression Database with Small Molecule Modulators.

7 months 3 weeks ago
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EDEn-Electroceutical Design Environment: Ion Channel Tissue Expression Database with Small Molecule Modulators.

iScience. 2018 Dec 11;11:42-56

Authors: Churchill CDM, Winter P, Tuszynski JA, Levin M

Abstract
The emerging field of bioelectricity has revealed numerous new roles for ion channels beyond the nervous system, which can be exploited for applications in regenerative medicine. Developing such biomedical interventions for birth defects, cancer, traumatic injury, and bioengineering first requires knowledge of ion channel targets expressed in tissues of interest. This information can then be used to select combinations of small molecule inhibitors and/or activators that manipulate the bioelectric state. Here, we provide an overview of electroceutical design environment (EDEn), the first bioinformatic platform that facilitates the design of such therapeutic strategies. This database includes information on ion channels and ion pumps, linked to known chemical modulators and their properties. The database also provides information about the expression levels of the ion channels in over 100 tissue types. The graphical interface allows the user to readily identify chemical entities that can alter the electrical properties of target cells and tissues.

PMID: 30590250 [PubMed - as supplied by publisher]

Synthesis of small peptide compounds, molecular docking, and inhibitory activity evaluation against phosphatases PTP1B and SHP2.

7 months 3 weeks ago
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Synthesis of small peptide compounds, molecular docking, and inhibitory activity evaluation against phosphatases PTP1B and SHP2.

Drug Des Devel Ther. 2018;12:4139-4147

Authors: Kostrzewa T, Sahu KK, Gorska-Ponikowska M, Tuszynski JA, Kuban-Jankowska A

Abstract
Background: The protein tyrosine phosphatases PTP1B and SHP2 are promising drug targets in treatment design for breast cancer. Searching for specific inhibitors of their activity has recently become the challenge of many studies. Previous work has indicated that the promising PTP inhibitors may be small compounds that are able to bind and interact with amino residues from the binding site.
Purpose: The main goal of our study was to synthesize and analyze the effect of selected small peptide inhibitors on oncogenic PTP1B and SHP2 enzymatic activity and viability of MCF7 breast cancer cells. We also performed computational analysis of peptides binding with allosteric sites of PTP1B and SHP2 phosphatases.
Methods: We measured the inhibitory activity of compounds utilizing recombinant enzymes and MCF7 cell line. Computational analysis involved docking studies of binding conformation and interactions of inhibitors with allosteric sites of phosphatases.
Results: The results showed that the tested compounds decrease the enzymatic activity of phosphatases PTP1B and SHP2 with IC50 values in micromolar ranges. We observed higher inhibitory activity of dipeptides than tripeptides. Phe-Asp was the most effective against SHP2 enzymatic activity, with IC50=5.2±0.4 µM. Micromolar concentrations of tested dipeptides also decreased the viability of MCF7 breast cancer cells, with higher inhibitory activity observed for the Phe-Asp peptide. Moreover, the peptides tested were able to bind and interact with allosteric sites of PTP1B and SHP2 phosphatases.
Conclusion: Our research showed that small peptide compounds can be considered for the design of specific inhibitors of oncogenic protein tyrosine phosphatases.

PMID: 30584278 [PubMed - indexed for MEDLINE]

Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents.

8 months 4 weeks ago
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Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents.

Cells. 2018 Nov 19;7(11):

Authors: Majcher U, Klejborowska G, Kaik M, Maj E, Wietrzyk J, Moshari M, Preto J, Tuszynski JA, Huczyński A

Abstract
Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin.

PMID: 30463236 [PubMed]

Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives.

9 months 2 weeks ago
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Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives.

Cells. 2018 Nov 01;7(11):

Authors: Majcher U, Klejborowska G, Moshari M, Maj E, Wietrzyk J, Bartl F, Tuszynski JA, Huczyński A

Abstract
Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells.

PMID: 30388878 [PubMed]

Synthesis, antiproliferative activity and molecular docking of thiocolchicine urethanes.

10 months 3 weeks ago
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Synthesis, antiproliferative activity and molecular docking of thiocolchicine urethanes.

Bioorg Chem. 2018 12;81:553-566

Authors: Majcher U, Urbaniak A, Maj E, Moshari M, Delgado M, Wietrzyk J, Bartl F, Chambers TC, Tuszynski JA, Huczyński A

Abstract
A number of naturally occurring compounds such as paclitaxel, vinblastine, combretastatin, and colchicine exert their therapeutic effect by changing the dynamics of tubulin and its polymer form, microtubules. The identification of tubulin as a potential target for anticancer drugs has led to extensive research followed by clinical development of numerous compounds from several families. In this paper we report on the design, synthesis and in vitro evaluation of a group of thiocolchicine derivatives, modified at ring-B, labelled here compounds 4-14. These compounds have been obtained in a simple reaction of 7-deacetyl-10-thiocolchicine 3 with eleven different alcohols in the presence of triphosgene. These novel agents have been checked for anti-proliferative activity against four human cancer cell lines and their mode of action has been confirmed as colchicine binding site inhibition (CBSI) using molecular docking. Molecular simulations provided rational tubulin binding models for the tested compounds. On the basis of in vitro tests, derivatives 4-8 and 14 demonstrated the highest potency against MCF-7, LoVo and A549 tumor cell lines (IC50 values = 0.009-0.014 μM). They were more potent and characterized by a higher selectivity index than several standard chemotherapeutics including cisplatin and doxorubicin as well as unmodified colchicine. Further, studies revealed that colchicine and its several derivatives arrested MCF-7 cells in mitosis, while its selected derivatives caused microtubule depolymerization.

PMID: 30248507 [PubMed - indexed for MEDLINE]

Tubulin's response to external electric fields by molecular dynamics simulations.

11 months ago
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Tubulin's response to external electric fields by molecular dynamics simulations.

PLoS One. 2018;13(9):e0202141

Authors: Timmons JJ, Preto J, Tuszynski JA, Wong ET

Abstract
Tubulin heterodimers are the building blocks of microtubules and disruption of their dynamics is exploited in the treatment of cancer. Electric fields at certain frequencies and magnitudes are believed to do the same. Here, the tubulin dimer's response to external electric fields was determined by atomistic simulation. External fields from 50 to 750 kV/cm, applied for 10 ns, caused significant conformational rearrangements that were dependent upon the field's directionality. Charged and flexible regions, including the α:H1-B2 loop, β:M-loop, and C-termini, were susceptible. Closer inspection of the α:H1-B2 loop in lower strength fields revealed that these effects were consistent and proportional to field strength, and the findings indicate that external electric fields modulate the stability of microtubules through conformational changes to key loops involved in lateral contacts. We also find evidence that tubulin's curvature and elongation are affected, and external electric fields may bias tubulin towards depolymerization.

PMID: 30231050 [PubMed - indexed for MEDLINE]

Virtual screening using covalent docking to find activators for G245S mutant p53.

11 months 1 week ago
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Virtual screening using covalent docking to find activators for G245S mutant p53.

PLoS One. 2018;13(9):e0200769

Authors: Omar SI, Lepre MG, Morbiducci U, Deriu MA, Tuszynski JA

Abstract
TP53 is the most mutated gene in all cancers. The mutant protein also accumulates in cells. The high frequency of p53 mutations makes the protein a promising target for anti-cancer therapy. Only a few molecules have been found, using in vitro screening, to reactivate the mutant protein. APR-246 is currently the most successful mutant p53 activator, which reactivates the transcriptional activity of p53 by covalently binding to C124 of the protein. We have recently created in silico models of G245S-mp53 in its apo and DNA-bound forms. In this paper we further report on our in silico screening for potential activators of G245S-mp53. We filtered the ZINC15 database (13 million compounds) to only include drug-like molecules with moderate to standard reactivity. Our filtered database of 130,000 compounds was screened using the DOCKTITE protocol in the Molecular Operating Environment software. We performed covalent docking at C124 of G245S-mp53 to identify potential activators of the mutant protein. The docked compounds were ranked using a consensus scoring approach. We also used ADMET Predictor™ to predict pharmacokinetics and the possible toxicities of the compounds. Our screening procedure has identified compounds, mostly thiosemicarbazones and halo-carbonyls, with the best potential as G245S-mp53 activators, which are described in this work. Based on its binding scores and ADMET risk score, compound 2 is likely to have the best potential as a G245S-mp53 activator compared to the other top hits.

PMID: 30192754 [PubMed - indexed for MEDLINE]

Nonlinear calcium ion waves along actin filaments control active hair-bundle motility.

11 months 2 weeks ago
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Nonlinear calcium ion waves along actin filaments control active hair-bundle motility.

Biosystems. 2018 Nov;173:181-190

Authors: Tuszynski JA, Sataric MV, Sekulic DL, Sataric BM, Zdravkovic S

Abstract
Calcium ions (Ca2+) tune and control numerous diverse aspects of cochlear and vestibular physiological processes. This paper is focused on the Ca2+ control of mechanotransduction in sensory hair cells in the context of polyelectrolyte properties of actin filaments within the hair-bundles of inner ear. These actin filaments appear to serve as efficient pathways for the flow of Ca2+ ions inside stereocilia. We showed how this can be utilized for tuning of force-generating myosin motors. In an established model, we unified the Ca2+ nonlinear dynamics involved in the control of myosin adaptation motors with mechanical displacements of hair-bundles. The model shows that the characteristic time scales fit reasonably well with the available experimental data for spontaneous oscillations in the inner ear. This scenario promises to fill a gap in our understanding of the role of Ca2+ ions in the regulation of processes in the auditory cells of the inner ear.

PMID: 30179640 [PubMed - indexed for MEDLINE]

Integration of intracellular signaling: Biological analogues of wires, processors and memories organized by a centrosome 3D reference system.

11 months 3 weeks ago
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Integration of intracellular signaling: Biological analogues of wires, processors and memories organized by a centrosome 3D reference system.

Biosystems. 2018 Nov;173:191-206

Authors: Barvitenko N, Lawen A, Aslam M, Pantaleo A, Saldanha C, Skverchinskaya E, Regolini M, Tuszynski JA

Abstract
BACKGROUND: Myriads of signaling pathways in a single cell function to achieve the highest spatio-temporal integration. Data are accumulating on the role of electromechanical soliton-like waves in signal transduction processes. Theoretical studies strongly suggest feasibility of both classical and quantum computing involving microtubules.
AIM: A theoretical study of the role of the complex composed of the plasma membrane and the microtubule-based cytoskeleton as a system that transmits, stores and processes information.
METHODS: Theoretical analysis presented here refers to (i) the Penrose-Hameroff theory of consciousness (Orchestrated Objective Reduction; Orch OR), (ii) the description of the centrosome as a reference system for construction of the 3D map of the cell proposed by Regolini, (iii) the Heimburg-Jackson model of the nerve pulse propagation along axons' lipid bilayer as soliton-like electro-mechanical waves.
RESULTS AND CONCLUSION: The ideas presented in this paper provide a qualitative model for the decision-making processes in a living cell undergoing a differentiation process.
OUTLOOK: This paper paves the way for the real-time live-cell observation of information processing by microtubule-based cytoskeleton and cell fate decision making.

PMID: 30142359 [PubMed - indexed for MEDLINE]

Using Spectral Representation to Classify Proteins' Conformational States.

1 year 1 month ago
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Using Spectral Representation to Classify Proteins' Conformational States.

Int J Mol Sci. 2018 Jul 18;19(7):

Authors: Saberi Fathi SM, Tuszynski JA

Abstract
Numerous proteins are molecular targets for drug action and hence are important in drug discovery. Structure-based computational drug discovery relies on detailed information regarding protein conformations for subsequent drug screening in silico. There are two key issues in analyzing protein conformations in virtual screening. The first considers the protein's conformational change in response to physical and chemical conditions. The second is the protein's atomic resolution reconstruction from X-ray crystallography or nuclear magnetic resonance (NMR) data. In this latter problem, information is needed regarding the sample's position relative to the source of X-rays. Here, we introduce a new measure for classifying protein conformational states using spectral representation and Wigner's D-functions. Predictions based on the new measure are in good agreement with conformational states of proteins. These results could also be applied to improve conformational alignment of the snapshots given by protein crystallography.

PMID: 30021967 [PubMed - indexed for MEDLINE]

A computational approach for predicting off-target toxicity of antiviral ribonucleoside analogues to mitochondrial RNA polymerase.

1 year 3 months ago
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A computational approach for predicting off-target toxicity of antiviral ribonucleoside analogues to mitochondrial RNA polymerase.

J Biol Chem. 2018 06 22;293(25):9696-9705

Authors: Freedman H, Winter P, Tuszynski J, Tyrrell DL, Houghton M

Abstract
In the development of antiviral drugs that target viral RNA-dependent RNA polymerases, off-target toxicity caused by the inhibition of the human mitochondrial RNA polymerase (POLRMT) is a major liability. Therefore, it is essential that all new ribonucleoside analogue drugs be accurately screened for POLRMT inhibition. A computational tool that can accurately predict NTP binding to POLRMT could assist in evaluating any potential toxicity and in designing possible salvaging strategies. Using the available crystal structure of POLRMT bound to an RNA transcript, here we created a model of POLRMT with an NTP molecule bound in the active site. Furthermore, we implemented a computational screening procedure that determines the relative binding free energy of an NTP analogue to POLRMT by free energy perturbation (FEP), i.e. a simulation in which the natural NTP molecule is slowly transformed into the analogue and back. In each direction, the transformation was performed over 40 ns of simulation on our IBM Blue Gene Q supercomputer. This procedure was validated across a panel of drugs for which experimental dissociation constants were available, showing that NTP relative binding free energies could be predicted to within 0.97 kcal/mol of the experimental values on average. These results demonstrate for the first time that free-energy simulation can be a useful tool for predicting binding affinities of NTP analogues to a polymerase. We expect that our model, together with similar models of viral polymerases, will be very useful in the screening and future design of NTP inhibitors of viral polymerases that have no mitochondrial toxicity.

PMID: 29739852 [PubMed - indexed for MEDLINE]