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

1 year 2 months ago
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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]

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

1 year 2 months ago
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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]

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

1 year 2 months ago
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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]

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

1 year 2 months ago
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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]

Designing and Testing of Novel Taxanes to Probe the Highly Complex Mechanisms by Which Taxanes Bind to Microtubules and Cause Cytotoxicity to Cancer Cells.

1 year 2 months ago
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Designing and Testing of Novel Taxanes to Probe the Highly Complex Mechanisms by Which Taxanes Bind to Microtubules and Cause Cytotoxicity to Cancer Cells.

PLoS One. 2015;10(6):e0129168

Authors: St George M, Ayoub AT, Banerjee A, Churchill CD, Winter P, Klobukowski M, Cass CE, Ludueña RF, Tuszynski JA, Damaraju S

Abstract
Our previous work identified an intermediate binding site for taxanes in the microtubule nanopore. The goal of this study was to test derivatives of paclitaxel designed to bind to this intermediate site differentially depending on the isotype of β-tubulin. Since β-tubulin isotypes have tissue-dependent expression--specifically, the βIII isotype is very abundant in aggressive tumors and much less common in normal tissues--this is expected to lead to tubulin targeted drugs that are more efficacious and have less side effects. Seven derivatives of paclitaxel were designed and four of these were amenable for synthesis in sufficient purity and yield for further testing in breast cancer model cell lines. None of the derivatives studied were superior to currently used taxanes, however computer simulations provided insights into the activity of the derivatives. Our results suggest that neither binding to the intermediate binding site nor the final binding site is sufficient to explain the activities of the derivative taxanes studied. These findings highlight the need to iteratively improve on the design of taxanes based on their activity in model systems. Knowledge gained on the ability of the engineered drugs to bind to targets and bring about activity in a predictable manner is a step towards personalizing therapies.

PMID: 26052950 [PubMed - indexed for MEDLINE]

Possible role of electrodynamic interactions in long-distance biomolecular recognition.

1 year 2 months ago
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Possible role of electrodynamic interactions in long-distance biomolecular recognition.

Phys Rev E Stat Nonlin Soft Matter Phys. 2015 May;91(5):052710

Authors: Preto J, Pettini M, Tuszynski JA

Abstract
The issue of retarded long-range resonant interactions between two molecules with oscillating dipole moments is revisited within the framework of classical electrodynamics. By taking advantage of a theorem in complex analysis, we present a simple method to calculate the frequencies of the normal modes, which are then used to estimate the interaction potential. The possibility that such interactions play a non-negligible role in ensuring the effective functioning of the biomolecular functions is investigated. On the basis of experimental results reported in the literature and simple numerical estimates, it is found that long-range interactions involving electromagnetic fields of frequencies 0.1-1THz could be temporarily activated despite radiation losses and solvent dissipation. Moreover, the theoretical background used to derive the mentioned interactions sheds light on Fröhlich's theory of selective long-range forces between biomolecules. At variance with a long-standing belief, we show that sizable resonant long-range interactions may exist only if the interacting system is out of thermal equilibrium.

PMID: 26066202 [PubMed - indexed for MEDLINE]

Diseases caused by defects of energy level and loss of coherence in living cells.

1 year 2 months ago
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Diseases caused by defects of energy level and loss of coherence in living cells.

Electromagn Biol Med. 2015;34(2):151-5

Authors: Jandová A, Pokorný J, Pokorný J, Kobilková J, Nedbalová M, Čoček A, Jelínek F, Vrba J, Vrba J, Dohnalová A, Kytnarová J, Tuszyński JA, Foletti A

Abstract
Human and animal diseases are brought about by pathological alterations of production, composition, and conformation of macromolecules and structures in cells. Additional contributing factors include changes in physiological states caused by disturbances of energy supply, energy transduction, energy dissipation in moving or oscillating parts, and parasitic energy consumption. Disturbances of energy states may endanger existence of the system. The cell-mediated immunity (CMI) response of T lymphocytes correlating with their adherence properties was examined using antigen prepared from the serum of inbred laboratory mice strain C3H H(2k) infected with lactate dehydrogenase elevating (LDH) virus. LDH virus is a parasite on the cellular energy system. Significant CMI response was elicited in T lymphocytes prepared from the blood of patients with cancer of different phenotypes, acute myocardial infarctions, schizophrenia, and recurrent spontaneous abortions in early pregnancy from unknown reasons. The CMI response is assumed to monitor transferred information about decreased levels of energy states and decoherence in the cells caused by mitochondrial malfunction, parasitic consumption, production of lactate, and possibly other disturbances. The LDH virus infection or similar pathological processes caused by different agents might be connected with the diseases and monitored by the examined CMI response. A large amount of mitoses with chromosome defects in aborted fetuses suggest increased mutability of genomes caused by defective energy states.

PMID: 26098528 [PubMed - indexed for MEDLINE]

Inactivation of Protein Tyrosine Phosphatases by Peracids Correlates with the Hydrocarbon Chain Length.

1 year 2 months ago
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Inactivation of Protein Tyrosine Phosphatases by Peracids Correlates with the Hydrocarbon Chain Length.

Cell Physiol Biochem. 2015;36(3):1069-83

Authors: Kuban-Jankowska A, Gorska M, Tuszynski JA, Churchill CD, Winter P, Klobukowski M, Wozniak M

Abstract
BACKGROUND/AIMS: Protein tyrosine phosphatases are crucial enzymes controlling numerous physiological and pathophysiological events and can be regulated by oxidation of the catalytic domain cysteine residue. Peracids are highly oxidizing compounds, and thus may induce inactivation of PTPs. The aim of the present study was to evaluate the inhibitory effect of peracids with different length of hydrocarbon chain on the activity of selected PTPs.
METHODS: The enzymatic activity of human CD45, PTP1B, LAR, bacterial YopH was assayed under the cell-free conditions, and activity of cellular CD45 in human Jurkat cell lysates. The molecular docking and molecular dynamics were performed to evaluate the peracids binding to the CD45 active site.
RESULTS: Here we demonstrate that peracids reduce enzymatic activity of recombinant CD45, PTP1B, LAR, YopH and cellular CD45. Our studies indicate that peracids are more potent inhibitors of CD45 than hydrogen peroxide (with an IC50 value equal to 25 nM for peroctanoic acid and 8 µM for hydrogen peroxide). The experimental data show that the inactivation caused by peracids is dependent on hydrocarbon chain length of peracids with maximum inhibitory effect of medium-chain peracids (C8-C12 acyl chain), which correlates with calculated binding affinities to the CD45 active site.
CONCLUSION: Peracids are potent inhibitors of PTPs with the strongest inhibitory effect observed for medium-chain peracids.

PMID: 26112900 [PubMed - indexed for MEDLINE]

A unified approach to computational drug discovery.

1 year 2 months ago
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A unified approach to computational drug discovery.

Drug Discov Today. 2015 Nov;20(11):1328-36

Authors: Tseng CY, Tuszynski J

Abstract
It has been reported that a slowdown in the development of new medical therapies is affecting clinical outcomes. The FDA has thus initiated the Critical Path Initiative project investigating better approaches. We review the current strategies in drug discovery and focus on the advantages of the maximum entropy method being introduced in this area. The maximum entropy principle is derived from statistical thermodynamics and has been demonstrated to be an inductive inference tool. We propose a unified method to drug discovery that hinges on robust information processing using entropic inductive inference. Increasingly, applications of maximum entropy in drug discovery employ this unified approach and demonstrate the usefulness of the concept in the area of pharmaceutical sciences.

PMID: 26189935 [PubMed - indexed for MEDLINE]

α-Synuclein dimer structures found from computational simulations.

1 year 2 months ago
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α-Synuclein dimer structures found from computational simulations.

Biochimie. 2015 Sep;116:133-40

Authors: Sahu KK, Woodside MT, Tuszynski JA

Abstract
Dimer formation is likely the first step in the oligomerization of α-synuclein in Lewy bodies. In order to prevent α-synuclein aggregation, knowledge of the atomistic structures of possible α-synuclein dimers and the interaction affinity between the dimer domains is a necessary prerequisite in the process of rational design of dimerization inhibitors. Using computational methodology, we have investigated several possible α-synuclein dimer structures, focusing on dimers formed from α-helical forms of the protein found when it is membrane-bound, and dimers formed from β-sheet conformations predicted by simulations. Structures and corresponding binding affinities for the interacting monomers in possible α-synuclein dimers, along with properties including the contributions from different interaction energies and the radii of gyration, were found through molecular docking followed by MD simulations and binding-energy calculations. We found that even though α-synuclein is highly charged, hydrophobic contributions play a significant role in stabilizing dimers.

PMID: 26193124 [PubMed - indexed for MEDLINE]

On the possible quantum role of serotonin in consciousness.

1 year 2 months ago
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On the possible quantum role of serotonin in consciousness.

J Integr Neurosci. 2015 Sep;14(3):295-308

Authors: Tonello L, Cocchi M, Gabrielli F, Tuszynski JA

Abstract
Cell membrane's fatty acids (FAs) have been carefully investigated in neurons and platelets in order to study a possible connection to psychopathologies. An important link between the FA distribution and membrane dynamics appears to emerge with the cytoskeleton dynamics. Microtubules (MTs) in particular have been implicated in some recent quantum consciousness models and analyses. The recently proposed quantum model of Craddock et al. (2014) states that MTs possess structural and functional characteristics that are consistent with collective quantum coherent excitations in the aromatic groups of their tryptophan residues. These excitations are consistent with a clocking mechanism on a sub-nanosecond scale. This mechanism and analogous phenomena in light-harvesting complexes in plants and bacteria, are induced by photons and have been touted as evidence of quantum processes in biology. A possible source of intra-cellular photons could be membrane lipid peroxidation processes, so the FA profile could then be linked to the bio-photon emission. The model presented here suggests new ways to understand the role serotonin plays in relation to FAs. In plants, tryptophan conversion of light to exciton energy can participate in the directional orientation of leaves toward sunlight. Since serotonin is structurally similar to tryptophan, in the human brain, neurons could use tryptophan to capture photons and also use serotonin to initiate movement toward the source of light. Hence, we postulate two possible new roles for serotonin: (1) as an antioxidant, in order to counter-balance the oxidative effect of FAs, and (2) to participate in quantum interactions with MTs, in the same way as anesthetics and psychoactive compounds have been recently shown to act. In this latter case, the FA profile could provide an indirect measure of serotonin levels.

PMID: 26227538 [PubMed - indexed for MEDLINE]

Analysis of the binding mode of laulimalide to microtubules: Establishing a laulimalide-tubulin pharmacophore.

1 year 2 months ago
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Analysis of the binding mode of laulimalide to microtubules: Establishing a laulimalide-tubulin pharmacophore.

J Biomol Struct Dyn. 2016 Jul;34(7):1455-69

Authors: Churchill CD, Klobukowski M, Tuszynski JA

Abstract
Laulimalide (LA) is a microtubule-stabilizing agent, currently in preclinical studies. However, studying the binding of this species and successfully synthesizing potent analogues have been challenging. The LA binding site is located between tubulin protofilaments, and therefore LA is in contact with two adjacent [Formula: see text]-tubulin units. Here, an improved model of the binding mode of LA in microtubules is presented, using the newly available crystal structure pose and an extended tubulin heterodimer complex, as well as molecular dynamics simulations. With this model, a series of LA analogues developed by Mooberry and coworkers are also analyzed in order to establish important pharmacophores in LA binding and cytotoxicity. In the side chain, [Formula: see text]-[Formula: see text] interactions are important contributors to LA binding, as are water-mediated hydrogen bonds. An intramolecular hydrogen bond is correlated with high cytotoxicity, and is dependent on macrocycle conformation. Therefore, while the epoxide and olefin groups in the macrocycle do not engage in specific interactions with the protein, they are essential contributions to an active macrocycle conformation, and therefore potency. Calculations reveal that a balance in binding affinity is important for LA activity, where the more potent compounds have larger interactions with the adjacent tubulin unit than the less-active analogs. Several modifications are suggested for the rational design of LA analogues that should not disrupt the active macrocycle conformation.

PMID: 26230757 [PubMed - indexed for MEDLINE]

The use of compressive sensing and peak detection in the reconstruction of microtubules length time series in the process of dynamic instability.

1 year 2 months ago
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The use of compressive sensing and peak detection in the reconstruction of microtubules length time series in the process of dynamic instability.

Comput Biol Med. 2015 Oct 01;65:25-33

Authors: Mahrooghy M, Yarahmadian S, Menon V, Rezania V, Tuszynski JA

Abstract
Microtubules (MTs) are intra-cellular cylindrical protein filaments. They exhibit a unique phenomenon of stochastic growth and shrinkage, called dynamic instability. In this paper, we introduce a theoretical framework for applying Compressive Sensing (CS) to the sampled data of the microtubule length in the process of dynamic instability. To reduce data density and reconstruct the original signal with relatively low sampling rates, we have applied CS to experimental MT lament length time series modeled as a Dichotomous Markov Noise (DMN). The results show that using CS along with the wavelet transform significantly reduces the recovery errors comparing in the absence of wavelet transform, especially in the low and the medium sampling rates. In a sampling rate ranging from 0.2 to 0.5, the Root-Mean-Squared Error (RMSE) decreases by approximately 3 times and between 0.5 and 1, RMSE is small. We also apply a peak detection technique to the wavelet coefficients to detect and closely approximate the growth and shrinkage of MTs for computing the essential dynamic instability parameters, i.e., transition frequencies and specially growth and shrinkage rates. The results show that using compressed sensing along with the peak detection technique and wavelet transform in sampling rates reduces the recovery errors for the parameters.

PMID: 26275388 [PubMed - indexed for MEDLINE]

Redox process is crucial for inhibitory properties of aurintricarboxylic acid against activity of YopH: virulence factor of Yersinia pestis.

1 year 2 months ago
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Redox process is crucial for inhibitory properties of aurintricarboxylic acid against activity of YopH: virulence factor of Yersinia pestis.

Oncotarget. 2015 Jul 30;6(21):18364-73

Authors: Kuban-Jankowska A, Sahu KK, Niedzialkowski P, Gorska M, Tuszynski JA, Ossowski T, Wozniak M

Abstract
YopH is a bacterial protein tyrosine phosphatase, which is essential for the viability and pathogenic virulence of the plague-causing Yersinia sp. bacteria. Inactivation of YopH activity would lead to the loss of bacterial pathogenicity. We have studied the inhibitory properties of aurintricarboxylic acid (ATA) against YopH phosphatase and found that at nanomolar concentrations ATA reversibly decreases the activity of YopH. Computational docking studies indicated that in all binding poses ATA binds in the YopH active site. Molecular dynamics simulations showed that in the predicted binding pose, ATA binds to the essential Cys403 and Arg409 residues in the active site and has a stronger binding affinity than the natural substrate (pTyr). The cyclic voltammetry experiments suggest that ATA reacts remarkably strongly with molecular oxygen. Additionally, the electrochemical reduction of ATA in the presence of a negative potential from -2.0 to 2.5 V generates a current signal, which is observed for hydrogen peroxide. Here we showed that ATA indicates a unique mechanism of YopH inactivation due to a redox process. We proposed that the potent inhibitory properties of ATA are a result of its strong binding in the YopH active site and in situ generation of hydrogen peroxide near catalytic cysteine residue.

PMID: 26286963 [PubMed - indexed for MEDLINE]

Modeling the energetic cost of cancer as a result of altered energy metabolism: implications for cachexia.

1 year 2 months ago
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Modeling the energetic cost of cancer as a result of altered energy metabolism: implications for cachexia.

Theor Biol Med Model. 2015 Sep 15;12:17

Authors: Friesen DE, Baracos VE, Tuszynski JA

Abstract
BACKGROUND: Cachexia affects most patients with incurable cancer. We hypothesize that in metastatic cancer the mass of the tumor as well as its level of anaerobic energy metabolism play a critical role in describing its energetic cost, which results in elevated resting energy expenditure and glucose utilization, leading to cachexia. Prior models of cancer cachexia may have underestimated the specific energetic cost of cancer as they have not taken the range of tumor mass and anaerobic energy metabolism fully into account.
METHODS: We therefore modelled the energetic cost of cancer as a function of the percentage of energy the cancer produces anaerobically, based on resting energy expenditure, glucose turnover, glucose recycling, and oxygen consumption in cancer patients found in previous studies.
RESULTS: Data from two clinical studies where tumor burden was estimated and resting energy expenditure or oxygen consumption were measured lead to a broad range of estimates of tumor cost from 190 to 470 kcal/kg tumor/day. These values will vary based of the percentage of energy the cancer produces anaerobically (from 0 to 100%), which in and of itself can alter the cost over a 2 to 3-fold range. In addition to the tumor cost/kg and the degree of anaerobic metabolism, the impact on a given individual patient will depend on tumor burden, which can exceed 1 kg in advanced metastatic disease. Considering these dimensions of tumor cost we are able to produce a 2-dimensional map of potential values, with an overall range of 100-1400 kcal/day.
CONCLUSIONS: Quantifying the energetic cost of cancer may benefit an understanding of the tumor's causation of cachexia. Our estimates of the range of tumor cost include values that are higher than prior estimates and suggest that in metastatic disease the tumor cost could be expected to eclipse attempts to stabilize energy balance through nutrition support or by drug therapies. Tumor mass and the percentage of anaerobic metabolism in the tumor contribute to the cost of the tumor on the body and potentially lead directly to negative energy balance and increased muscle wasting.

PMID: 26370269 [PubMed - indexed for MEDLINE]

The physiological concentration of ferrous iron (II) alters the inhibitory effect of hydrogen peroxide on CD45, LAR and PTP1B phosphatases.

1 year 2 months ago
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The physiological concentration of ferrous iron (II) alters the inhibitory effect of hydrogen peroxide on CD45, LAR and PTP1B phosphatases.

Biometals. 2015 Dec;28(6):975-86

Authors: Kuban-Jankowska A, Gorska M, Jaremko L, Jaremko M, Tuszynski JA, Wozniak M

Abstract
Hydrogen peroxide is an important regulator of protein tyrosine phosphatase activity via reversible oxidation. However, the role of iron in this reaction has not been yet elucidated. Here we compare the influence of hydrogen peroxide and the ferrous iron (reagent for Fenton reaction) on the enzymatic activity of recombinant CD45, LAR, PTP1B phosphatases and cellular CD45 in Jurkat cells. The obtained results show that ferrous iron (II) is potent inhibitor of CD45, LAR and PTP1B, but the inhibitory effect is concentration dependent. We found that the higher concentrations of ferrous iron (II) increase the inactivation of CD45, LAR and PTP1B phosphatase caused by hydrogen peroxide, but the addition of the physiological concentration (500 nM) of ferrous iron (II) has even a slightly preventive effect on the phosphatase activity against hydrogen peroxide.

PMID: 26407665 [PubMed - indexed for MEDLINE]

Conformational fluctuations of the AXH monomer of Ataxin-1.

1 year 2 months ago
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Conformational fluctuations of the AXH monomer of Ataxin-1.

Proteins. 2016 Jan;84(1):52-9

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

Abstract
In this paper, we report the results of molecular dynamics simulations of AXH monomer of Ataxin-1. The AXH domain plays a crucial role in Ataxin-1 aggregation, which accompanies the initiation and progression of Spinocerebellar ataxia type 1. Our simulations involving both classical and replica exchange molecular dynamics, followed by principal component analysis of the trajectories obtained, reveal substantial conformational fluctuations of the protein structure, especially in the N-terminal region. We show that these fluctuations can be generated by thermal noise since the free energy barriers between conformations are small enough for thermally stimulated transitions. In agreement with the previous experimental findings, our results can be considered as a basis for a future design of ataxin aggregation inhibitors that will require several key conformations identified in the present study as molecular targets for ligand binding.

PMID: 26522012 [PubMed - indexed for MEDLINE]

Entropic analysis reveals a connection between the recurrence of cancer and chemotherapy.

1 year 2 months ago
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Entropic analysis reveals a connection between the recurrence of cancer and chemotherapy.

Saudi J Biol Sci. 2015 Nov;22(6):674-8

Authors: Tseng CY, Tuszynski J

Abstract
In this study, we proposed an entropic analysis to overcome limitations of conventional statistical methods to analyze clinical data for cancer patients who experienced relapse of tumors following chemotherapy. We have applied this entropic method to reveal potential mechanisms that lead to a relapse of Wilms' tumor in pediatric patients. Results indicate β-tubulin isotype III up-regulation is likely the primary cause of the relapse.

PMID: 26586992 [PubMed]

Isolation of soluble scFv antibody fragments specific for small biomarker molecule, L-Carnitine, using phage display.

1 year 2 months ago
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Isolation of soluble scFv antibody fragments specific for small biomarker molecule, L-Carnitine, using phage display.

J Immunol Methods. 2016 Jan;428:9-19

Authors: Abou El-Magd RM, Vozza NF, Tuszynski JA, Wishart DS

Abstract
Isolation of single chain antibody fragment (scFv) clones from naïve Tomlinson I+J phage display libraries that specifically bind a small biomarker molecule, L-Carnitine, was performed using iterative affinity selection procedures. L-Carnitine has been described as a conditionally essential nutrient for humans. Abnormally high concentrations of L-Carnitine in urine are related to many health disorders including diabetes mellitus type 2 and lung cancer. ELISA-based affinity characterization results indicate that selectants preferentially bind to L-Carnitine in the presence of key bioselecting component materials and closely related L-Carnitine derivatives. In addition, the affinity results were confirmed using biophysical fluorescence quenching for tyrosine residues in the V segment. Small-scale production of the soluble fragment yielded 1.3mg/L using immunopure-immobilized protein A affinity column. Circular Dichroism data revealed that the antibody fragment (Ab) represents a folded protein that mainly consists of β-sheets. These novel antibody fragments may find utility as molecular affinity interface receptors in various electrochemical biosensor platforms to provide specific L-Carnitine binding capability with potential applications in metabolomic devices for companion diagnostics and personalized medicine applications. It may also be used in any other biomedical application where detection of the L-Carnitine level is important.

PMID: 26608419 [PubMed - indexed for MEDLINE]