Brain and Human Body Modeling 2020: Computational Human Models Presented at EMBC 2019 and the BRAIN Initiative® 2019 Meeting

2 hours 40 minutes ago
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Brain and Human Body Modeling 2020: Computational Human Models Presented at EMBC 2019 and the BRAIN Initiative® 2019 Meeting

Book. 2021

Authors: Makarov SN, Noetscher GM, Nummenmaa A

Abstract
Since approved by the FDA for the treatment of glioblastoma brain cancer in 2015, tumor-treating fields (TTFields) have rapidly become the fourth modality to treat cancer, along with surgery, chemotherapy, and radiation [1]. TTFields are now in clinical trials for a variety of cancer types. While efficacy has been proven in the clinic, the higher efficacy is demonstrated in vitro and in animal models, which indicates much greater clinical efficacy is possible. To attain the great promise of TTFields, uncovering the mechanisms of action (MoA) is necessary.


PMID: 32966029

Testing amino acid-codon affinity hypothesis using molecular docking.

2 hours 40 minutes ago
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Testing amino acid-codon affinity hypothesis using molecular docking.

Biosystems. 2020 Sep 20;:104251

Authors: Moghadam SA, Preto J, Klobukowski M, Tuszynski JA

Abstract
Genetic code refers to a set of rules that assign trinucleotides called codons to amino acids in the process of protein synthesis. Investigating the genetic code's logic and its evolutionary origin has always been both intriguing and challenging. While the correspondence rules between codons and amino acids in the genetic code are well-known, it is still unclear whether those assignments can be explained based on energetic or/and entropic arguments. As an attempt at deciphering basic thermodynamic rules governing DNA translation, we used molecular docking to investigate the ability of amino acids to bind to their corresponding anticodon compared to other codons. The total number of 1280 direct docking interactions have been performed for each amino acid-codon/anti-codon case to find whether the amino acids have a preference to bind to their cognate anticodons or codons. Based on docking scores which are expected to correlate with binding affinity, no correlation with genetic correspondence rules was observed suggesting a more subtle process, other than direct binding, to explain codon-amino-acid specificity.

PMID: 32966852 [PubMed - as supplied by publisher]

A new method for protein characterization and classification using geometrical features for 3D face analysis: an example of tubulin structures.

1 month 1 week ago
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A new method for protein characterization and classification using geometrical features for 3D face analysis: an example of tubulin structures.

Proteins. 2020 Aug 11;:

Authors: Di Grazia L, Aminpour M, Vezzetti E, Rezania V, Marcolin F, Tuszynski JA

Abstract
This paper reports on the results of research aimed to translate biometric 3D face recognition concepts and algorithms into the field of protein biophysics in order to precisely and rapidly classify morphological features of protein surfaces. Both human faces and protein surfaces are free-forms and some descriptors used in differential geometry can be used to describe them applying the principles of feature extraction developed for computer vision and pattern recognition. The first part of this study focused on building the protein dataset using a simulation tool and performing feature extraction using novel geometrical descriptors. The second part tested the method on two examples, first involved a classification of tubulin isotypes and the second compared tubulin with the FtsZ protein, which is its bacterial analogue. An additional test involved several unrelated proteins. Different classification methodologies have been used: a classic approach with a Support Vector Machine (SVM) classifier and an unsupervised learning with a k-means approach. The best result was obtained with SVM and the radial basis function (RBF) kernel. The results are significant and competitive with the state-of-the-art protein classification methods. This leads to a new methodological direction in protein structure analysis. This article is protected by copyright. All rights reserved.

PMID: 32779779 [PubMed - as supplied by publisher]

New Series of Double-Modified Colchicine Derivatives: Synthesis, Cytotoxic Effect and Molecular Docking.

1 month 2 weeks ago
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New Series of Double-Modified Colchicine Derivatives: Synthesis, Cytotoxic Effect and Molecular Docking.

Molecules. 2020 Aug 02;25(15):

Authors: Krzywik J, Aminpour M, Maj E, Mozga W, Wietrzyk J, Tuszyński JA, Huczyński A

Abstract
Colchicine is a well-known anticancer compound showing antimitotic effect on cells. Its high cytotoxic activity against different cancer cell lines has been demonstrated many times. In this paper we report the syntheses and spectroscopic analyses of novel colchicine derivatives obtained by structural modifications at C7 (carbon-nitrogen single bond) and C10 (methylamino group) positions. All the obtained compounds have been tested in vitro to determine their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX, and BALB/3T3 cell lines. The majority of obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin and cisplatin against the tested cancerous cell lines. Additionally, most of the presented derivatives were able to overcome the resistance of LoVo/DX cells. Additionally, their mode of binding to β-tubulin was evaluated in silico. Molecular docking studies showed that apart from the initial amides 1 and 2, compound 14, which had the best antiproliferative activity (IC50 = 0.1-1.6 nM), stood out also in terms of its predicted binding energy and probably binds best into the active site of βI-tubulin isotype.

PMID: 32748887 [PubMed - in process]

Design, synthesis and in vitro cell-free/cell-based biological evaluations of novel ERCC1-XPF inhibitors targeting DNA repair pathway.

1 month 3 weeks ago
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Design, synthesis and in vitro cell-free/cell-based biological evaluations of novel ERCC1-XPF inhibitors targeting DNA repair pathway.

Eur J Med Chem. 2020 Jul 22;204:112658

Authors: Elmenoufy AH, Gentile F, Jay D, Karimi-Busheri F, Yang X, Soueidan OM, Mani RS, Ciniero G, Tuszynski JA, Weinfeld M, West FG

Abstract
The structure-specific ERCC1-XPF endonuclease is essential for repairing bulky DNA lesions and helix distortions induced by UV radiation, which forms cyclobutane pyrimidine dimers (CPDs), or chemicals that crosslink DNA strands such as cyclophosphamide and platinum-based chemotherapeutic agents. Inhibition of the ERCC1-XPF endonuclease activity has been shown to sensitize cancer cells to these chemotherapeutic agents. In this study, we have conducted a structure activity relationship analysis based around the previously identified hit compound, 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-methylpiperazin1-yl)methyl)phenol (F06), as a reference compound. Three different series of compounds have been rationally designed and successfully synthesized through various modifications on three different sites of F06 based on the corresponding suggestions of the previous pharmacophore model. The in vitro screening results revealed that 2-chloro-9-((3-((4-(2-(dimethylamino)ethyl)piperazin-1-yl)methyl)-4-hydroxyphenyl)amino)acridin-2-ol (B9) has a potent inhibitory effect on the ERCC1-XPF activity (IC50 = 0.49 μM), showing 3-fold improvement in inhibition activity compared to F06. In addition, B9 not only displayed better binding affinity to the ERCC1-XPF complex but also had the capacity to potentiate the cytotoxicity effect of UV radiation and inhibiting the nucleotide excision repair, by the inhibition of removal of CPDs, and cyclophosphamide toxicity to colorectal cancer cells.

PMID: 32738410 [PubMed - as supplied by publisher]

Comparative Analysis, Structural Insights, and Substrate/Drug Interaction of CYP128A1 in Mycobacterium tuberculosis.

2 months 1 week ago
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Comparative Analysis, Structural Insights, and Substrate/Drug Interaction of CYP128A1 in Mycobacterium tuberculosis.

Int J Mol Sci. 2020 Jul 08;21(14):

Authors: Ngcobo NS, Chiliza ZE, Chen W, Yu JH, Nelson DR, Tuszynski JA, Preto J, Syed K

Abstract
Cytochrome P450 monooxygenases (CYPs/P450s) are well known for their role in organisms' primary and secondary metabolism. Among 20 P450s of the tuberculosis-causing Mycobacterium tuberculosis H37Rv, CYP128A1 is particularly important owing to its involvement in synthesizing electron transport molecules such as menaquinone-9 (MK9). This study employs different in silico approaches to understand CYP128 P450 family's distribution and structural aspects. Genome data-mining of 4250 mycobacterial species has revealed the presence of 2674 CYP128 P450s in 2646 mycobacterial species belonging to six different categories. Contrast features were observed in the CYP128 gene distribution, subfamily patterns, and characteristics of the secondary metabolite biosynthetic gene cluster (BGCs) between M. tuberculosis complex (MTBC) and other mycobacterial category species. In all MTBC species (except one) CYP128 P450s belong to subfamily A, whereas subfamily B is predominant in another four mycobacterial category species. Of CYP128 P450s, 78% was a part of BGCs with CYP124A1, or together with CYP124A1 and CYP121A1. The CYP128 family ranked fifth in the conservation ranking. Unique amino acid patterns are present at the EXXR and CXG motifs. Molecular dynamic simulation studies indicate that the CYP128A1 bind to MK9 with the highest affinity compared to the azole drugs analyzed. This study provides comprehensive comparative analysis and structural insights of CYP128A1 in M. tuberculosis.

PMID: 32650369 [PubMed - as supplied by publisher]

Actin networks voltage circuits.

2 months 4 weeks ago
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Actin networks voltage circuits.

Phys Rev E. 2020 May;101(5-1):052314

Authors: Siccardi S, Adamatzky A, Tuszyński J, Huber F, Schnauß J

Abstract
Filaments of the cellular protein actin can form bundles, which can conduct ionic currents as well as mechanical and voltage solitons. These inherent properties can be utilized to generate computing circuits solely based on self-assembled actin bundle structures. Starting with experimentally observed networks of actin bundles, we model their network structure in terms of edges and nodes. We compute and discuss the main electrical parameters, considering the bundles as electrical wires with either low or high filament densities. A set of equations describing the network is solved with several initial conditions. Input voltages, which can be considered as information bits, are applied in a set of points and output voltages are computed in another set of positions. We consider both an idealized situation, where pointlike electrodes can be inserted in any points of the bundles and a more realistic case, where electrodes lay on a surface and have typical dimensions available in the industry. We find that in both cases such a system can implement the main logical gates and a finite state machine.

PMID: 32575228 [PubMed]

A search for the physical basis of the genetic code.

4 months 2 weeks ago
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A search for the physical basis of the genetic code.

Biosystems. 2020 May 04;:104148

Authors: Moghadam SA, Klobukowski M, Tuszynski JA

Abstract
DNA contains the genetic code, which provides complete information about the synthesis of proteins in every living cell. Each gene encodes for a corresponding protein but most of the DNA sequence is non-coding. In addition to this non-coding part of the DNA, there is another redundancy, namely a multiplicity of DNA triplets (codons) corresponding to code for a given amino acid. In this paper we investigate possible physical reasons for the coding redundancy, by exploring free energy considerations and abundance probabilities as potential insights.

PMID: 32380130 [PubMed - as supplied by publisher]

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design.

4 months 3 weeks ago
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Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design.

Int J Mol Sci. 2020 Apr 28;21(9):

Authors: Bzówka M, Mitusińska K, Raczyńska A, Samol A, Tuszyński JA, Góra A

Abstract
The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar severe acute respiratory syndrome (SARS) Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins showed major differences in both shape and size, indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site's conformational changes during the simulation time indicated its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicated that the virus' mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.

PMID: 32353978 [PubMed - indexed for MEDLINE]

Synthesis, Antiproliferative Activity and Molecular Docking Studies of Novel Doubly Modified Colchicine Amides and Sulfonamides as Anticancer Agents.

5 months 1 week ago
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Synthesis, Antiproliferative Activity and Molecular Docking Studies of Novel Doubly Modified Colchicine Amides and Sulfonamides as Anticancer Agents.

Molecules. 2020 Apr 14;25(8):

Authors: Krzywik J, Mozga W, Aminpour M, Janczak J, Maj E, Wietrzyk J, Tuszyński JA, Huczyński A

Abstract
Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX and BALB/3T3 cell lines. Additionally, the activity of the studied compounds was investigated using computational methods involving molecular docking of the colchicine derivatives to β-tubulin. The majority of the obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin or cisplatin against tested cancer cell lines. Furthermore, molecular modeling studies of the obtained compounds revealed their possible binding modes into the colchicine binding site of tubulin.

PMID: 32295119 [PubMed - in process]

Cell death and survival due to cytotoxic exposure modelled as a two-state Ising system.

5 months 2 weeks ago
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Cell death and survival due to cytotoxic exposure modelled as a two-state Ising system.

R Soc Open Sci. 2020 Feb;7(2):191578

Authors: Arbabi Moghadam S, Rezania V, Tuszynski JA

Abstract
Cancer chemotherapy agents are assessed for their therapeutic utility primarily by their ability to cause apoptosis of cancer cells and their potency is given by an IC50 value. Chemotherapy uses both target-specific and systemic-action drugs and drug combinations to treat cancer. It is important to judiciously choose a drug type, its dosage and schedule for optimized drug selection and administration. Consequently, the precise mathematical formulation of cancer cells' response to chemotherapy may assist in the selection process. In this paper, we propose a mathematical description of the cancer cell response to chemotherapeutic agent exposure based on a time-tested physical model of two-state multiple-component systems near criticality. We describe the Ising model methodology and apply it to a diverse panel of cytotoxic drugs administered against numerous cancer cell lines in a dose-response manner. The analysed dataset was generated by the Netherlands Translational Research Center B.V. (Oncolines). This approach allows for an accurate and consistent analysis of cytotoxic agents' effects on cancer cell lines and reveals the presence or absence of the bystander effect through the interaction constant. By calculating the susceptibility function, we see the value of IC50 coinciding with the peak of this measure of the system's sensitivity to external perturbations.

PMID: 32257323 [PubMed]

Personalized therapy design for systemic lupus erythematosus based on the analysis of protein-protein interaction networks.

6 months ago
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Personalized therapy design for systemic lupus erythematosus based on the analysis of protein-protein interaction networks.

PLoS One. 2020;15(3):e0226883

Authors: Brant EJ, Rietman EA, Klement GL, Cavaglia M, Tuszynski JA

Abstract
We analyzed protein expression data for Lupus patients, which have been obtained from publicly available databases. A combination of systems biology and statistical thermodynamics approaches was used to extract topological properties of the associated protein-protein interaction networks for each of the 291 patients whose samples were used to provide the molecular data. We have concluded that among the many proteins that appear to play critical roles in this pathology, most of them are either ribosomal proteins, ubiquitination pathway proteins or heat shock proteins. We propose some of the proteins identified in this study to be considered for drug targeting.

PMID: 32191711 [PubMed - indexed for MEDLINE]

In silico Investigations of the Mode of Action of Novel Colchicine Derivatives Targeting β-Tubulin Isotypes: A Search for a Selective and Specific β-III Tubulin Ligand.

6 months 1 week ago
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In silico Investigations of the Mode of Action of Novel Colchicine Derivatives Targeting β-Tubulin Isotypes: A Search for a Selective and Specific β-III Tubulin Ligand.

Front Chem. 2020;8:108

Authors: Pallante L, Rocca A, Klejborowska G, Huczynski A, Grasso G, Tuszynski JA, Deriu MA

Abstract
The cardinal role of microtubules in cell mitosis makes them interesting drug targets for many pharmacological treatments, including those against cancer. Moreover, different expression patterns between cell types for several tubulin isotypes represent a great opportunity to improve the selectivity and specificity of the employed drugs and to design novel compounds with higher activity only on cells of interest. In this context, tubulin isotype βIII represents an excellent target for anti-tumoral therapies since it is overexpressed in most cancer cells and correlated with drug resistance. Colchicine is a well-known antimitotic agent, which is able to bind the tubulin dimer and to halt the mitotic process. However, it shows high toxicity also on normal cells and it is not specific for isotype βIII. In this context, the search for colchicine derivatives is a matter of great importance in cancer research. In this study, homology modeling techniques, molecular docking, and molecular dynamics simulations have been employed to characterize the interaction between 55 new promising colchicine derivatives and tubulin isotype βIII. These compounds were screened and ranked based on their binding affinity and conformational stability in the colchicine binding site of tubulin βIII. Results from this study point the attention on an amide of 4-chlorine thiocolchicine. This colchicine-derivative is characterized by a unique mode of interaction with tubulin, compared to all other compounds considered, which is primarily characterized by the involvement of the α-T5 loop, a key player in the colchicine binding site. Information provided by the present study may be particularly important in the rational design of colchicine-derivatives targeting drug resistant cancer phenotypes.

PMID: 32154219 [PubMed]

Liver Bioreactor Design Issues of Fluid Flow and Zonation, Fibrosis, and Mechanics: A Computational Perspective.

6 months 2 weeks ago
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Liver Bioreactor Design Issues of Fluid Flow and Zonation, Fibrosis, and Mechanics: A Computational Perspective.

J Funct Biomater. 2020 Feb 28;11(1):

Authors: Rezania V, Coombe D, Tuszynski J

Abstract
Tissue engineering, with the goal of repairing or replacing damaged tissue and organs, has continued to make dramatic science-based advances since its origins in the late 1980's and early 1990's. Such advances are always multi-disciplinary in nature, from basic biology and chemistry through physics and mathematics to various engineering and computer fields. This review will focus its attention on two topics critical for tissue engineering liver development: (a) fluid flow, zonation, and drug screening, and (b) biomechanics, tissue stiffness, and fibrosis, all within the context of 3D structures. First, a general overview of various bioreactor designs developed to investigate fluid transport and tissue biomechanics is given. This includes a mention of computational fluid dynamic methods used to optimize and validate these designs. Thereafter, the perspective provided by computer simulations of flow, reactive transport, and biomechanics responses at the scale of the liver lobule and liver tissue is outlined, in addition to how bioreactor-measured properties can be utilized in these models. Here, the fundamental issues of tortuosity and upscaling are highlighted, as well as the role of disease and fibrosis in these issues. Some idealized simulations of the effects of fibrosis on lobule drug transport and mechanics responses are provided to further illustrate these concepts. This review concludes with an outline of some practical applications of tissue engineering advances and how efficient computational upscaling techniques, such as dual continuum modeling, might be used to quantify the transition of bioreactor results to the full liver scale.

PMID: 32121053 [PubMed]

Synthesis, biological evaluation and molecular docking studies of new amides of 4-chlorothiocolchicine as anticancer agents.

6 months 3 weeks ago
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Synthesis, biological evaluation and molecular docking studies of new amides of 4-chlorothiocolchicine as anticancer agents.

Bioorg Chem. 2020 Feb 13;97:103664

Authors: Klejborowska G, Urbaniak A, Maj E, Preto J, Moshari M, Wietrzyk J, Tuszynski JA, Chambers TC, Huczyński A

Abstract
Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and primary acute lymphoblastic leukemia (ALL) cells and they showed activity in the nanomolar range. The obtained IC50 values for novel derivatives were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies of colchicine and selected analogues were undertaken to indicate that they induced apoptotic cell death in ALL-5 cells. We also performed in silico studies to predict binding modes of the 4-chlorothiocolchicine derivatives to different β tubulin isotypes. The results indicate that select triple-modified 4-chlorothiocolchicine derivatives represent highly promising novel cancer chemotherapeutics.

PMID: 32106039 [PubMed - as supplied by publisher]

Using the Gibbs Function as a Measure of Human Brain Development Trends from Fetal Stage to Advanced Age.

7 months 1 week ago
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Using the Gibbs Function as a Measure of Human Brain Development Trends from Fetal Stage to Advanced Age.

Int J Mol Sci. 2020 Feb 07;21(3):

Authors: Rietman EA, Taylor S, Siegelmann HT, Deriu MA, Cavaglia M, Tuszynski JA

Abstract
We propose to use a Gibbs free energy function as a measure of the human brain development. We adopt this approach to the development of the human brain over the human lifespan: from a prenatal stage to advanced age. We used proteomic expression data with the Gibbs free energy to quantify human brain's protein-protein interaction networks. The data, obtained from BioGRID, comprised tissue samples from the 16 main brain areas, at different ages, of 57 post-mortem human brains. We found a consistent functional dependence of the Gibbs free energies on age for most of the areas and both sexes. A significant upward trend in the Gibbs function was found during the fetal stages, which is followed by a sharp drop at birth with a subsequent period of relative stability and a final upward trend toward advanced age. We interpret these data in terms of structure formation followed by its stabilization and eventual deterioration. Furthermore, gender data analysis has uncovered the existence of functional differences, showing male Gibbs function values lower than female at prenatal and neonatal ages, which become higher at ages 8 to 40 and finally converging at late adulthood with the corresponding female Gibbs functions.

PMID: 32046179 [PubMed - in process]

Investigation of the Electrical Properties of Microtubule Ensembles under Cell-Like Conditions.

7 months 2 weeks ago
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Investigation of the Electrical Properties of Microtubule Ensembles under Cell-Like Conditions.

Nanomaterials (Basel). 2020 Feb 05;10(2):

Authors: Kalra AP, Patel SD, Bhuiyan AF, Preto J, Scheuer KG, Mohammed U, Lewis JD, Rezania V, Shankar K, Tuszynski JA

Abstract
Microtubules are hollow cylindrical polymers composed of the highly negatively-charged (~23e), high dipole moment (1750 D) protein α, β- tubulin. While the roles of microtubules in chromosomal segregation, macromolecular transport, and cell migration are relatively well-understood, studies on the electrical properties of microtubules have only recently gained strong interest. Here, we show that while microtubules at physiological concentrations increase solution capacitance, free tubulin has no appreciable effect. Further, we observed a decrease in electrical resistance of solution, with charge transport peaking between 20-60 Hz in the presence of microtubules, consistent with recent findings that microtubules exhibit electric oscillations at such low frequencies. We were able to quantify the capacitance and resistance of the microtubules (MT) network at physiological tubulin concentrations to be 1.27 × 10-5 F and 9.74 × 104 Ω. Our results show that in addition to macromolecular transport, microtubules also act as charge storage devices through counterionic condensation across a broad frequency spectrum. We conclude with a hypothesis of an electrically tunable cytoskeleton where the dielectric properties of tubulin are polymerisation-state dependent.

PMID: 32033331 [PubMed]

Microtubules as Sub-Cellular Memristors.

7 months 2 weeks ago
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Microtubules as Sub-Cellular Memristors.

Sci Rep. 2020 Feb 07;10(1):2108

Authors: Tuszynski JA, Friesen D, Freedman H, Sbitnev VI, Kim H, Santelices I, Kalra AP, Patel SD, Shankar K, Chua LO

Abstract
Memristors represent the fourth electrical circuit element complementing resistors, capacitors and inductors. Hallmarks of memristive behavior include pinched and frequency-dependent I-V hysteresis loops and most importantly a functional dependence of the magnetic flux passing through an ideal memristor on its electrical charge. Microtubules (MTs), cylindrical protein polymers composed of tubulin dimers are key components of the cytoskeleton. They have been shown to increase solution's ionic conductance and re-orient in the presence of electric fields. It has been hypothesized that MTs also possess intrinsic capacitive and inductive properties, leading to transistor-like behavior. Here, we show a theoretical basis and experimental support for the assertion that MTs under specific circumstances behave consistently with the definition of a memristor. Their biophysical properties lead to pinched hysteretic current-voltage dependence as well a classic dependence of magnetic flux on electric charge. Based on the information about the structure of MTs we provide an estimate of their memristance. We discuss its significance for biology, especially neuroscience, and potential for nanotechnology applications.

PMID: 32034179 [PubMed - in process]

Dataset on interactions of membrane active agents with lipid bilayers.

7 months 2 weeks ago
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Dataset on interactions of membrane active agents with lipid bilayers.

Data Brief. 2020 Apr;29:105138

Authors: Ashrafuzzaman M, Tseng CY, Tuszynski JA

Abstract
We address drug interactions with lipids using in silico simulations and in vitro experiments. The data article provides extended explanations on molecular mechanisms behind membrane action of membrane-active agents (MAAs): antimicrobial peptides and chemotherapy drugs. Complete interpretation of the data is found in the associated original article 'charge-based interactions of antimicrobial peptides and general drugs with lipid bilayers' [1]. Data on molecular dynamic simulations of the drug lipid complexes are provided. Additional data and information are provided here to explain the connectivity among various information and techniques used for understanding of the membrane action and/or binding of MAAs including aptamers. Brief explanation has been provided on the possibility of achieving a converted triangle from newly discovered quadrangle, sides of which explain four different phenomena: 'membrane effects', 'detection and quantification', 'origin of energetics' and 'structure stability' while drug effects occur. Triangle or quadrangle corners represent various techniques that were applied.

PMID: 32016146 [PubMed]

Computer-Aided Drug Design of Small Molecule Inhibitors of the ERCC1-XPF Protein-Protein Interaction.

8 months 3 weeks ago
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Computer-Aided Drug Design of Small Molecule Inhibitors of the ERCC1-XPF Protein-Protein Interaction.

Chem Biol Drug Des. 2019 Dec 31;:

Authors: Gentile F, Elmenoufy AH, Ciniero G, Jay D, Karimi-Busheri F, Barakat KH, Weinfeld M, West FG, Tuszynski JA

Abstract
The heterodimer of DNA excision repair protein ERCC-1 and DNA repair endonuclease XPF (ERCC1-XPF) is a 5´-3´ structure-specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1-XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum-based and crosslinking agents, thus its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1-XPF interaction (Jordheim et al., 2013), to improve its binding to the target. We followed a multi-step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, B5, showed an improved half-maximum inhibitory concentration (IC50 ) value of 0.49 µM for the inhibition of ERCC1-XPF endonuclease activity, and lays the foundation for further testing and optimization. Also, the computational approach reported here can be used to develop DNA repair inhibitors targeting the ERCC1-XPF complex.

PMID: 31891209 [PubMed - as supplied by publisher]