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

2 days 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.

3 weeks 2 days 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.

1 month 1 week 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.

2 months 3 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.

3 months 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.

3 months 2 weeks 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.

3 months 3 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.

4 months 2 weeks 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.

4 months 3 weeks 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.

5 months 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.

5 months 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.

5 months 2 weeks 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.

5 months 3 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.

5 months 3 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.

5 months 4 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.

7 months 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]

Gibbs free energy of protein-protein interactions correlates with ATP production in cancer cells.

7 months 2 weeks ago
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Gibbs free energy of protein-protein interactions correlates with ATP production in cancer cells.

J Biol Phys. 2019 12;45(4):423-430

Authors: Golas SM, Nguyen AN, Rietman EA, Tuszynski JA

Abstract
In this paper, we analyze several cancer cell types from two seemingly independent angles: (a) the over-expression of various proteins participating in protein-protein interaction networks and (b) a metabolic shift from oxidative phosphorylation to glycolysis. We use large data sets to obtain a thermodynamic measure of the protein-protein interaction network, namely the associated Gibbs free energy. We find a strong inverse correlation between the percentage of energy production via oxidative phosphorylation and the Gibbs free energy of the protein networks. The latter is a measure of functional dysregulation within the cell. Our findings corroborate earlier indications that signaling pathway upregulation in cancer cells is linked to the metabolic shift known as the Warburg effect; hence, these two seemingly independent characteristics of cancer phenotype may be interconnected.

PMID: 31845118 [PubMed - indexed for MEDLINE]

Charge-based interactions of antimicrobial peptides and general drugs with lipid bilayers.

7 months 4 weeks ago
Related Articles

Charge-based interactions of antimicrobial peptides and general drugs with lipid bilayers.

J Mol Graph Model. 2019 Nov 27;95:107502

Authors: Ashrafuzzaman M, Tseng CY, Tuszynski JA

Abstract
Membrane-active agents (MAAs), such as antimicrobial peptides (AMPs) and chemotherapy drugs (CDs), induce ion pores/channels inside lipid bilayer membrane, as confirmed by standard electrophysiology experiments. A novel experimental method is described which detects agents directly at the membrane as confirmed for MAAs, CDs and aptamers. MAAs exhibit characteristic 'charge based' interactions with lipids. Electrostatic (ES) and van der Waals (vdW) contributions to the interaction energies have been estimated using molecular dynamics (MD) simulations. These results are consistent with the screened Coulomb interaction predictions recently developed for lipid bilayer binding of integral AMP channels. Energy- and distance-dependence of MAA-lipid interactions from MD simulations are represented by universal probability functions. A generalized model of MAA-lipid interactions is developed based on the charge and geometrical profiles of the participating lipids and AMPs. The corresponding driving force correlates directly with the stability of MAA-lipid structures as observed in electrophysiology experiments. We conclude that MAAs and similar agents that target lipid membranes exhibit physiological effects mainly due to ES and vdW interactions determined by their charge profiles.

PMID: 31805474 [PubMed - as supplied by publisher]

Brain and Human Body Modeling: Computational Human Modeling at EMBC 2018

8 months 2 weeks ago
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Brain and Human Body Modeling: Computational Human Modeling at EMBC 2018

Book. 2019

Authors: Makarov S, Horner M, Noetscher G

Abstract
This chapter presents an overview of electric conduction in living cells when viewed as a composition of bioelectric circuits. We review the cell’s components that are known to exhibit electric conduction properties and represent them as parts of a complex circuitry. In particular, we discuss conductivity of the membrane, ion channels, actin filaments, DNA, and microtubules, each of which play important roles in the biological functioning of the cell. A new picture emerges where electrical conduction within the cell is taking place in an integrated fashion and may explain synchronization and orchestration of the cell dynamics.


PMID: 31725231

Brain and Human Body Modeling: Computational Human Modeling at EMBC 2018

8 months 2 weeks ago
Related Articles

Brain and Human Body Modeling: Computational Human Modeling at EMBC 2018

Book. 2019

Authors: Makarov S, Horner M, Noetscher G

Abstract
Our goal is to uncover the mechanism underlying tumour-treating fields’ efficacy in killing cancer cells. Modelling the effects of these 200 kHz alternating current electric fields on tumour cell sub-structures has led us to focus on the microtubules (MTs), C-termini and the motor protein kinesin, which are integral to the critical functions of MT transport of proteins during the delicate orchestration of cell division (mitosis). Leading hypotheses of the TTFields’ mechanism that we are modelling include disruption of mitosis functions (such as the ‘kinesin walk’ along MTs), C-termini state transitions and MT polymerization.


PMID: 31725240