Experimental and computational study of the interaction of novel colchicinoids with a recombinant human αI/βI-tubulin heterodimer.

2 years 1 month ago
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Experimental and computational study of the interaction of novel colchicinoids with a recombinant human αI/βI-tubulin heterodimer.

Chem Biol Drug Des. 2013 Jul;82(1):60-70

Authors: Mane JY, Semenchenko V, Perez-Pineiro R, Winter P, Wishart D, Tuszynski JA

Abstract
The binding free energies on human tubulin of selected colchicine and thiocolchicine compounds were determined. Two methods were used for the determination of binding free energies: one is based on theoretical prediction simulating the dissociation of the compound from tubulin using a series of molecular dynamics simulations, and the other method involves a series of experiments that measured the affinity of the compound on a synthetically expressed and purified tubulin protein using a spectrofluorometric technique.

PMID: 23480279 [PubMed - indexed for MEDLINE]

Stochastic and Deterministic Models of Cellular p53 Regulation.

2 years 1 month ago
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Stochastic and Deterministic Models of Cellular p53 Regulation.

Front Oncol. 2013;3:64

Authors: Leenders GB, Tuszynski JA

Abstract
The protein p53 is a key regulator of cellular response to a wide variety of stressors. In cancer cells inhibitory regulators of p53 such as MDM2 and MDMX proteins are often overexpressed. We apply in silico techniques to better understand the role and interactions of these proteins in a cell cycle process. Furthermore we investigate the role of stochasticity in determining system behavior. We have found that stochasticity is able to affect system behavior profoundly. We also derive a general result for the way in which initially synchronized oscillating stochastic systems will fall out of synchronization with each other.

PMID: 23565502 [PubMed]

Small molecule inhibitors of ERCC1-XPF protein-protein interaction synergize alkylating agents in cancer cells.

2 years 1 month ago
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Small molecule inhibitors of ERCC1-XPF protein-protein interaction synergize alkylating agents in cancer cells.

Mol Pharmacol. 2013 Jul;84(1):12-24

Authors: Jordheim LP, Barakat KH, Heinrich-Balard L, Matera EL, Cros-Perrial E, Bouledrak K, El Sabeh R, Perez-Pineiro R, Wishart DS, Cohen R, Tuszynski J, Dumontet C

Abstract
The benefit of cancer chemotherapy based on alkylating agents is limited because of the action of DNA repair enzymes, which mitigate the damage induced by these agents. The interaction between the proteins ERCC1 and XPF involves two major components of the nucleotide excision repair pathway. Here, novel inhibitors of this interaction were identified by virtual screening based on available structures with use of the National Cancer Institute diversity set and a panel of DrugBank small molecules. Subsequently, experimental validation of the in silico screening was undertaken. Top hits were evaluated on A549 and HCT116 cancer cells. In particular, the compound labeled NSC 130813 [4-[(6-chloro-2-methoxy-9-acridinyl)amino]-2-[(4-methyl-1-piperazinyl)methyl]] was shown to act synergistically with cisplatin and mitomycin C; to increase UVC-mediated cytotoxicity; to modify DNA repair as indicated by the staining of phosphorylated H2AX; and to disrupt interaction between ERCC1 and XPF in cells. In addition, using the Biacore technique, we showed that this compound interacts with the domain of XPF responsible for interaction with ERCC1. This study shows that small molecules targeting the protein-protein interaction of ERCC1 and XPF can be developed to enhance the effects of alkylating agents on cancer cells.

PMID: 23580445 [PubMed - indexed for MEDLINE]

Determination of the optimal tubulin isotype target as a method for the development of individualized cancer chemotherapy.

2 years 1 month ago
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Determination of the optimal tubulin isotype target as a method for the development of individualized cancer chemotherapy.

Theor Biol Med Model. 2013 May 01;10:29

Authors: Ravanbakhsh S, Gajewski M, Greiner R, Tuszynski JA

Abstract
BACKGROUND: As microtubules are essential for cell growth and division, its constituent protein β-tubulin has been a popular target for various treatments, including cancer chemotherapy. There are several isotypes of human β-tubulin and each type of cell expresses its characteristic distribution of these isotypes. Moreover, each tubulin-binding drug has its own distribution of binding affinities over the various isotypes, which further complicates identifying the optimal drug selection. An ideal drug would preferentially bind only the tubulin isotypes expressed abundantly by the cancer cells, but not those in the healthy cells. Unfortunately, as the distributions of the tubulin isotypes in cancer cells overlap with those of healthy cells, this ideal scenario is clearly not possible. We can, however, seek a drug that interferes significantly with the isotype distribution of the cancer cell, but has only minor interactions with those of the healthy cells.
METHODS: We describe a quantitative methodology for identifying this optimal tubulin isotype profile for an ideal cancer drug, given the isotype distribution of a specific cancer type, as well as the isotype distributions in various healthy tissues, and the physiological importance of each such tissue.
RESULTS: We report the optimal isotype profiles for different types of cancer with various routes of delivery.
CONCLUSIONS: Our algorithm, which defines the best profile for each type of cancer (given the drug delivery route and some specified patient characteristics), will help to personalize the design of pharmaceuticals for individual patients. This paper is an attempt to explicitly consider the effects of the tubulin isotype distributions in both cancer and normal cell types, for rational chemotherapy design aimed at optimizing the drug's efficacy with minimal side effects.

PMID: 23634782 [PubMed - indexed for MEDLINE]

An integrated multidisciplinary model describing initiation of cancer and the Warburg hypothesis.

2 years 1 month ago
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An integrated multidisciplinary model describing initiation of cancer and the Warburg hypothesis.

Theor Biol Med Model. 2013 Jun 10;10:39

Authors: Rietman EA, Friesen DE, Hahnfeldt P, Gatenby R, Hlatky L, Tuszynski JA

Abstract
BACKGROUND: In this paper we propose a chemical physics mechanism for the initiation of the glycolytic switch commonly known as the Warburg hypothesis, whereby glycolytic activity terminating in lactate continues even in well-oxygenated cells. We show that this may result in cancer via mitotic failure, recasting the current conception of the Warburg effect as a metabolic dysregulation consequent to cancer, to a biophysical defect that may contribute to cancer initiation.
MODEL: Our model is based on analogs of thermodynamic concepts that tie non-equilibrium fluid dynamics ultimately to metabolic imbalance, disrupted microtubule dynamics, and finally, genomic instability, from which cancers can arise. Specifically, we discuss how an analog of non-equilibrium Rayleigh-Benard convection can result in glycolytic oscillations and cause a cell to become locked into a higher-entropy state characteristic of cancer.
CONCLUSIONS: A quantitative model is presented that attributes the well-known Warburg effect to a biophysical mechanism driven by a convective disturbance in the cell. Contrary to current understanding, this effect may precipitate cancer development, rather than follow from it, providing new insights into carcinogenesis, cancer treatment, and prevention.

PMID: 23758735 [PubMed - indexed for MEDLINE]

Biophysical insights into cancer transformation and treatment.

2 years 1 month ago
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Biophysical insights into cancer transformation and treatment.

ScientificWorldJournal. 2013;2013:195028

Authors: Pokorný J, Foletti A, Kobilková J, Jandová A, Vrba J, Vrba J, Nedbalová M, Čoček A, Danani A, Tuszyński JA

Abstract
Biological systems are hierarchically self-organized complex structures characterized by nonlinear interactions. Biochemical energy is transformed into work of physical forces required for various biological functions. We postulate that energy transduction depends on endogenous electrodynamic fields generated by microtubules. Microtubules and mitochondria colocalize in cells with microtubules providing tracks for mitochondrial movement. Besides energy transformation, mitochondria form a spatially distributed proton charge layer and a resultant strong static electric field, which causes water ordering in the surrounding cytosol. These effects create conditions for generation of coherent electrodynamic field. The metabolic energy transduction pathways are strongly affected in cancers. Mitochondrial dysfunction in cancer cells (Warburg effect) or in fibroblasts associated with cancer cells (reverse Warburg effect) results in decreased or increased power of the generated electromagnetic field, respectively, and shifted and rebuilt frequency spectra. Disturbed electrodynamic interaction forces between cancer and healthy cells may favor local invasion and metastasis. A therapeutic strategy of targeting dysfunctional mitochondria for restoration of their physiological functions makes it possible to switch on the natural apoptotic pathway blocked in cancer transformed cells. Experience with dichloroacetate in cancer treatment and reestablishment of the healthy state may help in the development of novel effective drugs aimed at the mitochondrial function.

PMID: 23844381 [PubMed - indexed for MEDLINE]

Similarity-based virtual screening for microtubule stabilizers reveals novel antimitotic scaffold.

2 years 1 month ago
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Similarity-based virtual screening for microtubule stabilizers reveals novel antimitotic scaffold.

J Mol Graph Model. 2013 Jul;44:188-96

Authors: Ayoub AT, Klobukowski M, Tuszynski J

Abstract
Microtubules are among the most studied and best characterized cancer targets identified to date. Many microtubule stabilizers have been introduced so far that work by disrupting the dynamic instability of microtubules causing mitotic block and apoptosis. However, most of these molecules, especially taxol and epothilone, suffer absorption, toxicity and/or resistance problems. Here we employ a novel similarity-based virtual screening approach in the hope of finding other microtubule stabilizers that perform better and have lower toxicity and resistance. Epothilones, discodermolide, eleutherobin and sarcodictyin A have been found to compete with taxanes for the β-tubulin binding site, which suggests common chemical features qualifying for that. Our approach was based on similarity screening against all these compounds and other microtubule stabilizers, followed by virtual screening against the taxol binding site. Some novel hits were found, together with a novel highly rigid molecular scaffold. After visual manipulations, redocking and rescoring of this novel scaffold, its affinity dramatically increased in a promising trend, which qualifies for biological testing.

PMID: 23871820 [PubMed - indexed for MEDLINE]

A physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model.

2 years 1 month ago
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A physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model.

Theor Biol Med Model. 2013 Sep 05;10:52

Authors: Rezania V, Marsh R, Coombe D, Tuszynski J

Abstract
We develop a physiologically-based lattice model for the transport and metabolism of drugs in the functional unit of the liver, called the lobule. In contrast to earlier studies, we have emphasized the dominant role of convection in well-vascularized tissue with a given structure. Estimates of convective, diffusive and reaction contributions are given. We have compared drug concentration levels observed exiting the lobule with their predicted detailed distribution inside the lobule, assuming that most often the former is accessible information while the latter is not.

PMID: 24007328 [PubMed - indexed for MEDLINE]

A physiologically-based flow network model for hepatic drug elimination II: variable lattice lobule models.

2 years 1 month ago
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A physiologically-based flow network model for hepatic drug elimination II: variable lattice lobule models.

Theor Biol Med Model. 2013 Sep 05;10:53

Authors: Rezania V, Marsh R, Coombe D, Tuszynski J

Abstract
We extend a physiologically-based lattice model for the transport and metabolism of drugs in the liver lobule (liver functional unit) to consider structural and spatial variability. We compare predicted drug concentration levels observed exiting the lobule with their detailed distribution inside the lobule, and indicate the role that structural variation has on these results. Liver zonation and its role on drug metabolism represent another aspect of structural inhomogeneity that we consider here. Since various liver diseases can be thought to produce such structural variations, our analysis gives insight into the role of disease on liver function and performance. These conclusions are based on the dominant role of convection in well-vascularized tissue with a given structure.

PMID: 24007357 [PubMed - indexed for MEDLINE]

Near death experiences: a multidisciplinary hypothesis.

2 years 1 month ago
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Near death experiences: a multidisciplinary hypothesis.

Front Hum Neurosci. 2013;7:533

Authors: Bókkon I, Mallick BN, Tuszynski JA

Abstract
Recently, we proposed a novel biophysical concept regarding on the appearance of brilliant lights during near death experiences (NDEs) (Bókkon and Salari, 2012). Specifically, perceiving brilliant light in NDEs has been proposed to arise due to the reperfusion that produces unregulated overproduction of free radicals and energetically excited molecules that can generate a transient enhancement of bioluminescent biophotons in different areas of the brain, including retinotopic visual areas. If this excess of bioluminescent photon emission exceeds a threshold in retinotopic visual areas, this can appear as (phosphene) lights because the brain interprets these intrinsic retinotopic bioluminescent photons as if they originated from the external physical world. Here, we review relevant literature that reported experimental studies (Imaizumi et al., 1984; Suzuki et al., 1985) that essentially support our previously published conception, i.e., that seeing lights in NDEs may be due to the transient enhancement of bioluminescent biophotons. Next, we briefly describe our biophysical visual representation model that may explain brilliant lights experienced during NDEs (by phosphenes as biophotons) and REM sleep associated dream-like intrinsic visual imageries through biophotons in NDEs. Finally, we link our biophysical visual representation notion to self-consciousness that may involve extremely low-energy quantum entanglements. This article is intended to introduce novel concepts for discussion and does not pretend to give the ultimate explanation for the currently unanswerable questions about matter, life and soul; their creation and their interrelationship.

PMID: 24062655 [PubMed]

A computational model for overcoming drug resistance using selective dual-inhibitors for aurora kinase A and its T217D variant.

2 years 1 month ago
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A computational model for overcoming drug resistance using selective dual-inhibitors for aurora kinase A and its T217D variant.

Mol Pharm. 2013 Dec 02;10(12):4572-89

Authors: Barakat KH, Huzil JT, Jordan KE, Evangelinos C, Houghton M, Tuszynski J

Abstract
The human Aurora kinase-A (AK-A) is an essential mitotic regulator that is frequently overexpressed in several cancers. The recent development of several novel AK-A inhibitors has been driven by the well-established association of this target with cancer development and progression. However, resistance and cross-reactivity with similar kinases demands an improvement in our understanding of key molecular interactions between the Aurora kinase-A substrate binding pocket and potential inhibitors. Here, we describe the implementation of state-of-the-art virtual screening techniques to discover a novel set of Aurora kinase-A ligands that are predicted to strongly bind not only to the wild type protein, but also to the T217D mutation that exhibits resistance to existing inhibitors. Furthermore, a subset of these computationally screened ligands was shown to be more selective toward the mutant variant over the wild type protein. The description of these selective subsets of ligands provides a unique pharmacological tool for the design of new drug regimens aimed at overcoming both kinase cross-reactivity and drug resistance associated with the Aurora kinase-A T217D mutation.

PMID: 24094068 [PubMed - indexed for MEDLINE]

Detailed computational study of the active site of the hepatitis C viral RNA polymerase to aid novel drug design.

2 years 1 month ago
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Detailed computational study of the active site of the hepatitis C viral RNA polymerase to aid novel drug design.

J Chem Inf Model. 2013 Nov 25;53(11):3031-43

Authors: Barakat KH, Law J, Prunotto A, Magee WC, Evans DH, Tyrrell DL, Tuszynski J, Houghton M

Abstract
The hepatitis C virus (HCV) RNA polymerase, NS5B, is a leading target for novel and selective HCV drug design. The enzyme has been the subject of intensive drug discovery aimed at developing direct acting antiviral (DAA) agents that inhibit its activity and hence prevent the virus from replicating its genome. In this study, we focus on one class of NS5B inhibitors, namely nucleos(t)ide mimetics. Forty-one distinct nucleotide structures have been modeled within the active site of NS5B for the six major HCV genotypes. Our comprehensive modeling protocol employed 287 different molecular dynamics simulations combined with the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) methodology to rank and analyze these structures for all genotypes. The binding interactions of the individual compounds have been investigated and reduced to the atomic level. The present study significantly refines our understanding of the mode of action of NS5B-nucleotide-inhibitors, identifies the key structural elements necessary for their activity, and implements the tools for ranking the potential of additional much needed novel inhibitors of NS5B.

PMID: 24116674 [PubMed - indexed for MEDLINE]

Bridging the gap between the technological singularity and mainstream medicine: highlighting a course on technology and the future of medicine.

2 years 1 month ago
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Bridging the gap between the technological singularity and mainstream medicine: highlighting a course on technology and the future of medicine.

Glob J Health Sci. 2013 Sep 09;5(6):112-25

Authors: Solez K, Bernier A, Crichton J, Graves H, Kuttikat P, Lockwood R, Marovitz WF, Monroe D, Pallen M, Pandya S, Pearce D, Saleh A, Sandhu N, Sergi C, Tuszynski J, Waugh E, White J, Woodside M, Wyndham R, Zaiane O, Zakus D

Abstract
The "technological singularity" is defined as that putative point in time forecasted to occur in the mid twenty-first century when machines will become smarter than humans, leading humans and machines to merge. It is hypothesized that this event will have a profound influence on medicine and population health. This work describes a new course on Technology and the Future of Medicine developed by a diverse, multi-disciplinary group of faculty members at a Canadian university. The course began as a continuous professional learning course and was later established as a recognized graduate course. We describe the philosophy of the course, the barriers encountered in course development, and some of the idiosyncratic solutions that were developed to overcome these, including the use of YouTube audience retention analytics. We hope that this report might provide a useful template for other institutions attempting to set up similar programs.

PMID: 24171879 [PubMed - indexed for MEDLINE]

An accurate method for prediction of protein-ligand binding site on protein surface using SVM and statistical depth function.

2 years 1 month ago
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An accurate method for prediction of protein-ligand binding site on protein surface using SVM and statistical depth function.

Biomed Res Int. 2013;2013:409658

Authors: Wang K, Gao J, Shen S, Tuszynski JA, Ruan J, Hu G

Abstract
Since proteins carry out their functions through interactions with other molecules, accurately identifying the protein-ligand binding site plays an important role in protein functional annotation and rational drug discovery. In the past two decades, a lot of algorithms were present to predict the protein-ligand binding site. In this paper, we introduce statistical depth function to define negative samples and propose an SVM-based method which integrates sequence and structural information to predict binding site. The results show that the present method performs better than the existent ones. The accuracy, sensitivity, and specificity on training set are 77.55%, 56.15%, and 87.96%, respectively; on the independent test set, the accuracy, sensitivity, and specificity are 80.36%, 53.53%, and 92.38%, respectively.

PMID: 24195070 [PubMed - indexed for MEDLINE]

A computationally designed DNA aptamer template with specific binding to phosphatidylserine.

2 years 1 month ago
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A computationally designed DNA aptamer template with specific binding to phosphatidylserine.

Nucleic Acid Ther. 2013 Dec;23(6):418-26

Authors: Ashrafuzzaman M, Tseng CY, Kapty J, Mercer JR, Tuszynski JA

Abstract
The phospholipid phosphatidylserine (PS) is an early marker exploited for detecting apoptosis (PS externalization in the cell membrane bilayer) and one factor that is associated with increased amyloid plaque deposition in transmissible spongiform encephalopathies (TSEs). PS can therefore be considered as a promising target for diagnosis or treatment of diseases. Aptamers (short nucleic acid sequences) are a particularly attractive class of materials among those currently considered for targeting PS. Here we applied an entropy based seed-and-grow strategy to design a DNA aptamer template to bind specifically to PS. The binding properties of designed aptamers were investigated computationally and experimentally. The studies identify the sequence, 5'-AAAGAC-3', as the preferred template for further modifications and studies toward its practical implementations.

PMID: 24279298 [PubMed - indexed for MEDLINE]

Homology and molecular dynamics models of toll-like receptor 7 protein and its dimerization.

2 years 1 month ago
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Homology and molecular dynamics models of toll-like receptor 7 protein and its dimerization.

Chem Biol Drug Des. 2014 Jun;83(6):656-65

Authors: Tseng CY, Gajewski M, Danani A, Tuszynski JA

Abstract
Toll-like receptor protein 7 is a transmembrane protein playing a crucial role in the signaling pathways involved in innate immunity. Its crystal structure is not yet available, but there are several proteins possessing domains of sufficiently high homology, which enabled us to build a model of the toll-like receptor protein 7 monomer and gain insights into dimer formation. To obtain a reliable structure prediction, we subjected this model to equilibration using molecular dynamics simulations. Furthermore, the equilibrated monomer structure was used to construct models of dimerization and to predict binding sites for small ligands. Docking studies were performed for some of the known toll-like receptor protein 7 ligands. We determined that a new homology model generated by the LOOPP server provides a good alternative to a previously reported model. Our docking results indicate that the addition of either imiquimod or 1V209 to a toll-like receptor protein 7 dimer changes an unfavorable interaction into a favorable one. We found that eight small molecules docked to two pockets in toll-like receptor protein 7 bind to both pockets at pH 7 and at pH 5.5. This work provides a realistic model that could be used for drug discovery aimed at finding toll-like receptor protein 7 dimerization activators, with potential clinical applications to a host of diseases, including cancer.

PMID: 24406029 [PubMed - indexed for MEDLINE]

Systematic identification and evolutionary analysis of catalytically versatile cytochrome p450 monooxygenase families enriched in model basidiomycete fungi.

2 years 1 month ago
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Systematic identification and evolutionary analysis of catalytically versatile cytochrome p450 monooxygenase families enriched in model basidiomycete fungi.

PLoS One. 2014;9(1):e86683

Authors: Syed K, Shale K, Pagadala NS, Tuszynski J

Abstract
Genome sequencing of basidiomycetes, a group of fungi capable of degrading/mineralizing plant material, revealed the presence of numerous cytochrome P450 monooxygenases (P450s) in their genomes, with some exceptions. Considering the large repertoire of P450s found in fungi, it is difficult to identify P450s that play an important role in fungal metabolism and the adaptation of fungi to diverse ecological niches. In this study, we followed Sir Charles Darwin's theory of natural selection to identify such P450s in model basidiomycete fungi showing a preference for different types of plant components degradation. Any P450 family comprising a large number of member P450s compared to other P450 families indicates its natural selection over other P450 families by its important role in fungal physiology. Genome-wide comparative P450 analysis in the basidiomycete species, Phanerochaete chrysosporium, Phanerochaete carnosa, Agaricus bisporus, Postia placenta, Ganoderma sp. and Serpula lacrymans, revealed enrichment of 11 P450 families (out of 68 P450 families), CYP63, CYP512, CYP5035, CYP5037, CYP5136, CYP5141, CYP5144, CYP5146, CYP5150, CYP5348 and CYP5359. Phylogenetic analysis of the P450 family showed species-specific alignment of P450s across the P450 families with the exception of P450s of Phanerochaete chrysosporium and Phanerochaete carnosa, suggesting paralogous evolution of P450s in model basidiomycetes. P450 gene-structure analysis revealed high conservation in the size of exons and the location of introns. P450s with the same gene structure were found tandemly arranged in the genomes of selected fungi. This clearly suggests that extensive gene duplications, particularly tandem gene duplications, led to the enrichment of selective P450 families in basidiomycetes. Functional analysis and gene expression profiling data suggest that members of the P450 families are catalytically versatile and possibly involved in fungal colonization of plant material. To our knowledge, this is the first report on the identification and comparative-evolutionary analysis of P450 families enriched in model basidiomycetes.

PMID: 24466198 [PubMed - indexed for MEDLINE]

Regulation of channel function due to physical energetic coupling with a lipid bilayer.

2 years 1 month ago
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Regulation of channel function due to physical energetic coupling with a lipid bilayer.

Biochem Biophys Res Commun. 2014 Mar 07;445(2):463-8

Authors: Ashrafuzzaman M, Tseng CY, Tuszynski JA

Abstract
Regulation of membrane protein functions due to hydrophobic coupling with a lipid bilayer has been investigated. An energy formula describing interactions between lipid bilayer and integral ion channels with different structures, which is based on the screened Coulomb interaction approximation, has been developed. Here the interaction energy is represented as being due to charge-based interactions between channel and lipid bilayer. The hydrophobic bilayer thickness channel length mismatch is found to induce channel destabilization exponentially while negative lipid curvature linearly. Experimental parameters related to channel dynamics are consistent with theoretical predictions. To measure comparable energy parameters directly in the system and to elucidate the mechanism at an atomistic level we performed molecular dynamics (MD) simulations of the ion channel forming peptide-lipid complexes. MD simulations indicate that peptides and lipids experience electrostatic and van der Waals interactions for short period of time when found within each other's proximity. The energies from these two interactions are found to be similar to the energies derived theoretically using the screened Coulomb and the van der Waals interactions between peptides (in ion channel) and lipids (in lipid bilayer) due to mainly their charge properties. The results of in silico MD studies taken together with experimental observable parameters and theoretical energetic predictions suggest that the peptides induce ion channels inside lipid membranes due to peptide-lipid physical interactions. This study provides a new insight helping better understand of the underlying mechanisms of membrane protein functions in cell membrane leading to important biological implications.

PMID: 24530910 [PubMed - indexed for MEDLINE]

A Refined Model of the HCV NS5A protein bound to daclatasvir explains drug-resistant mutations and activity against divergent genotypes.

2 years 1 month ago
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A Refined Model of the HCV NS5A protein bound to daclatasvir explains drug-resistant mutations and activity against divergent genotypes.

J Chem Inf Model. 2015 Feb 23;55(2):362-73

Authors: Barakat KH, Anwar-Mohamed A, Tuszynski JA, Robins MJ, Tyrrell DL, Houghton M

Abstract
Many direct-acting antiviral agents (DAAs) that selectively block hepatitis C virus (HCV) replication are currently under development. Among these agents is Daclatasvir, a first-in-class inhibitor targeting the NS5A viral protein. Although Daclatasvir is the most potent HCV antiviral molecule yet developed, its binding location and mode of binding remain unknown. The drug exhibits a low barrier to resistance mutations, particularly in genotype 1 viruses, but its efficacy against other genotypes is unclear. Using state-of-the-art modeling techniques combined with the massive computational power of Blue Gene/Q, we identified the atomic interactions of Daclatasvir within NS5A for different HCV genotypes and for several reported resistant mutations. The proposed model is the first to reveal the detailed binding mode of Daclatasvir. It also provides a tool to facilitate design of second generation drugs, which may confer less resistance and/or broader activity against HCV.

PMID: 24730573 [PubMed - indexed for MEDLINE]