Biyoinformatik ve Genetik Bölümü Koleksiyonu

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Citation Count: 30
Cis-cyclopropylamines as mechanism-based inhibitors of monoamine oxidases
(Wiley-Blackwell, 2015) Yelekçi, Kemal; Yelekçi, Kemal; Borrello, Maria Teresa; Ganesan, A.; Semina, Elena; De Kimpe, Norbert; Mangelinckx, Sven; Ramsay, Rona R.
Cyclopropylamines inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1) provide a useful structural scaffold for the design of mechanism-based inhibitors for treatment of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring the apparent affinity determined from docking experiments revealed little difference between the enantiomers. Using the racemate kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. For reversible inhibition most compounds gave high IC50 values with MAO A but sub-micromolar values with MAO B. After pre-incubation of the cyclopropylamine with the enzyme the inhibition was irreversible for both MAOA and MAOB and the activity was not restored by dilution. Spectral changes during inactivation of MAOA included bleaching at 456nm and an increased absorbance at 400nm consistent with flavin modification. These derivatives are MAOB-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine with an IC50 of 5nm for MAOB and 170nm for MAOA after 30min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine so may be studied as a lead for selective inhibitors of MAOB that do not inhibit LSD1.
Citation Count: 3
Coulomb corrections in the lepton-pair production in ultrarelativistic nuclear collisions
(Amer Physical Soc., 2005) Güçlu, Mehmet C.; Kovankaya, G.; Yılmaz, Melek
We solve the perturbative electron-positron pair production exactly by calculating the second-order Feynman diagrams. We compare our result with Born methods that include Coulomb corrections. We find that a small-momentum approximation is not adequate to obtain exact Coulomb corrections and higher-order terms should also be included. We also compare the impact parameter dependence cross sections.
Citation Count: 6
Critical phenomenon during photoinitiated gelation at different temperatures: A Photo-DSC study
(Elsevier Science, 2011) Dogruyol, Zekeriya; Arsu, Nergis; Dogruyol, Sevnur Keskin; Pekcan, Önder
The behaviour of photoinitiated radical polymerization of an 80 wt% epoxy diacrylate (EA) and 20 wt% tripropyleneglycoldiacrylate (TPGDA) mixture with 2-mercaptothioxanthone (TX-SH) photoinitiator was studied at different temperatures by using photo-differential scanning calorimetric (Photo-DSC) technique. All photopolymerization reactions were carried out under the same conditions. It was observed that all conversion curves during gelation at different temperatures present nice sigmoidal behaviour which suggests the application of the percolation model. Observations around the critical time called the glass transition point (t(g)) taken to reach the maximum rate of polymerization (Rp(max)) show that the gel fraction exponent (beta) obeyed the percolation model. The produced beta values were found to be around 0.50 predicting that the system under consideration belongs to the same universality class. However. Rp(max) and the final conversion (C(s)) values were found to increase when the temperature was increased up to a certain value. On the other hand t(g) values decreased and became saturated as the temperature was increased. (C) 2011 Elsevier B.V. All rights reserved.
Citation Count: 0
Design and synthesis of novel 2-pyrazoline analogues and their hMAO inhibitory activities
(Wiley-Blackwell, 2015) Yelekçi, Kemal; Evranos-Aksoz, Begum; Yabanoglu-Çiftçi, Samiye; Yelekçi, Kemal
[Abstract Not Available]
Citation Count: 0
Discovery of new azoles with potent activity against Candida spp. and Candida albicans biofilms through virtual screening
(Elsevier, 2020) Eşsiz, Şebnem; Kart, Didem; Öztürk, Naile; Kaynak, F. Betül; Gencel, Melis; Taşkor, Gülce; Karakurt, Arzu; Saraç, Selma; Eşsiz, Şebnem; Dalkara, Sevim
Systemic candidiasis is a rampant bloodstream infection ofCandidaspp. andC. albicansis the majorpathogen isolated from infected humans. Azoles, the most common class of antifungals which sufferfrom increasing resistance, and especially intrinsically resistant non-albicans Candida(NAC) species, actby inhibiting fungal lanosterol 14a-demethylase (CYP51). In this study we identified a number of azolecompounds in 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol/ethanone oxime ester structurethrough virtual screening using consensus scoring approach, synthesized and tested them for theirantifungal properties. We reached several hits with potent activity against azole-susceptible and azole-resistantCandidaspp. as well as biofilms ofC. albicans.5i's minimum inhibitor concentration (MIC) was0.125mg/ml againstC. albicans, 0.5mg/ml againstC. kruseiand 1mg/ml against azole-resistantC. tropicalisisolate. Considering the MIC values offluconazole against these fungi (0.5, 32 and 512mg/ml, respec-tively),5iemerged as a highly potent derivative. The minimum biofilm inhibitor concentration (MBIC) of5c,5j, and5pwere 0.5mg/ml (and5iwas 2mg/ml) againstC. albicansbiofilms, lower than that ofamphotericin B (4mg/ml), afirst-line antifungal with antibiofilm activity. In addition, the active com-pounds showed neglectable toxicity to human monocytic cell line. We further analyzed the dockingposes of the active compounds inC. albicansCYP51 (CACYP51) homology model catalytic site andidentified molecular interactions in agreement with those of known azoles with fungal CYP51s andmutagenesis studies of CACYP51. We observed the stability of CACYP51 in complex with5iin moleculardynamics simulations.©2019 Elsevier Masson SAS. All rights reserved.1. IntroductionSystemic candidiasis is a major public health issue, especiallywith immune-suppressed cases reaching high mortality rates. Themembers of the genusCandidaare the most frequently recoveredfrom human fungal infection andCandida albicans, so far, is theleading pathogen identified in nosocomial candidiasis [1]. Inaddition to increasing drug-resistant strains ofC. albicans, emer-gence of non-albicans Candidaspp. (NAC) complicate the treatmentof mycoses [2].C. tropicalisis among the NACs that show reducedsusceptibility tofirst-line antifungals reportedly leading to break-through fungemia among high-risk patients [3,4]. Also,C. kruseiisknown to be intrinsically resistant to a number of azoles includingfluconazole [5]. One of the several mechanisms of therapy-resistance is formation of biofilms, which are complex microor-ganism colonies enclosed in an exopolysaccharide matrix on bioticand non-biotic surfaces. Persistent biofilms make fungi much lesssusceptible to antifungal drugs compared to their planktonic formsfor a number of reasons [6e8]. Therefore it is essential to design*Corresponding author. Hacettepe University Faculty of Pharmacy, Departmentof Pharmaceutical Chemistry, 06100, Sihhiye, Ankara, Turkey.E-mail addresses:suat.sari@hacettepe.edu.tr,suat1039@gmail.com(S. Sari).Contents lists available atScienceDirectEuropean Journal of Medicinal Chemistryjournal homepage:http://www.elsevier.com/locate/ejmechhttps://doi.org/10.1016/j.ejmech.2019.06.0830223-5234/©2019 Elsevier Masson SAS. All rights reserved.European Journal of Medicinal Chemistry 179 (2019) 634e648
Citation Count: 5
Distinctive communication networks in inactive states of beta(2)-adrenergic receptor: Mutual information and entropy transfer analysis
(Wiley, 2020) Soğünmez, Nuray; Akten, Ebru Demet
Mutual information and entropy transfer analysis employed on two inactive states of human beta-2 adrenergic receptor (beta(2)-AR) unraveled distinct communication pathways. Previously, a so-called "highly" inactive state of the receptor was observed during 1.5 microsecond long molecular dynamics simulation where the largest intracellular loop (ICL3) was swiftly packed onto the G-protein binding cavity, becoming entirely inaccessible. Mutual information quantifying the degree of correspondence between backbone-C(alpha)fluctuations was mostly shared between intra- and extra-cellular loop regions in the original inactive state, but shifted to entirely different regions in this latest inactive state. Interestingly, the largest amount of mutual information was always shared among the mobile regions. Irrespective of the conformational state, polar residues always contributed more to mutual information than hydrophobic residues, and also the number of polar-polar residue pairs shared the highest degree of mutual information compared to those incorporating hydrophobic residues. Entropy transfer, quantifying the correspondence between backbone-C(alpha)fluctuations at different timesteps, revealed a distinctive pathway directed from the extracellular site toward intracellular portions in this recently exposed inactive state for which the direction of information flow was the reverse of that observed in the original inactive state where the mobile ICL3 and its intracellular surroundings drove the future fluctuations of extracellular regions.
Citation Count: 3
The effects of Dea:water ratio on the properties of ZnO nanofilms obtained by spin coating method
(Elsevier Science, 2014) Akkaya Arier, Ümit Özlem; Uysal, Bengü Özuğur
In this work the ZnO were fabricated with the sol-gel spin coating method and the effects of the Dea:water ratios on the properties of the as-prepared ZnO thin films were determined by using a X-ray diffractometer transmission electron microscope scanning electron microscope atomic force microscope ultraviolet-visible spectrophotometer and spectrophotometer. Experimental results indicated that the Dea:water ratio affected the structural and optical properties of the ZnO films considerably. The activation energy for the particle growth of ZnO nanofilms and the effects of the Dea:water ratios on the band gap values of the ZnO films were investigated. The film has an activation energy of 26.3 kJ/mol and optical band gap of 3.27-3.31 eV is proportional to the Dea:water ratio. (c) 2014 Elsevier Ltd. All rights reserved.
Citation Count: 32
Effects of GNP addition on optical properties and band gap energies of PMMA films
(Wiley, 2019) Mergen, Ömer Bahadır; Arda, Ertan; Kara, Selim; Pekcan, Önder
In this study the effects of graphene nanoplatelet (GNP) doping on the optical parameters (absorption coefficient alpha and extinction coefficient k) and the optical transition energies (optical band gap and Urbach energies) of poly(methyl methacrylate)/graphene nanoplatelet (PMMA/GNP) composite films were studied. PMMA/GNP composite films with various GNP mass fractions were prepared by spin coating technique. The absorbance (A) changes of the prepared composites were measured by using UV-Vis technique. The alpha and k values of the composites were obtained from UV-Vis data. The observed rapid increase in A values in UV-region were associated with the optical transitions of GNP electrons from valence to conduction band. The direct (E-d) and indirect (E-i) optical band gap energies of the composites were determined by using Tauc method. Both of the band gap energies were decreased when the GNP content in the PMMA matrix is increased. The decrease in the band gap energies was interpreted as evidence of increased conductivity of the composites. Additionally energies of the band tails (Urbach energy) were calculated. It was seen that the Urbach energy levels were increased with GNP content. POLYM. COMPOS. 40:1862-1869 2019. (c) 2018 Society of Plastics Engineers
Citation Count: 4
The Electrochromic Performances of Single Phase VO2 Nanoparticled Films
(Elsevier Science SA, 2016) Akkaya Arier, Ümit Özlem; Uysal, Bengü Özuğur
In the present work pure phase vanadium oxide VO2 nanoparticled films were synthesized using acetate based sol-gel precursors. The effect of the water: Vanadyl acetylacetonate ratio on electrochemical and structural properties of nanostructured vanadium oxide films was examined. The X-ray diffraction studies indicated that very strong crystallization of the VO2 monoclinic phase occurred for the as-deposited films at the annealing temperature of 500 degrees C. According to the atomic force microscopy and scanning electron microscopy measurements the size and morphology of the granular structured film depend on the water: Vanadyl acetylacetonate ratio. I-V curve spectra were used to compute several characteristics of the films coated on indium tin oxide substrates such as the optical density color efficiency and diffusion coefficient. Even though water: Vanadyl acetylacetonate ratio of 0.1 is expected to give the highest color efficiency value (33 cm(2)/C) higher diffusion coefficient (3.15 x 10(-12) cm(2)/s) is observed in the ratio of 0.01. As a result the correlation between the ratios and electrochromic properties of the films was established. (C) 2016 Elsevier B.V. All rights reserved.
Citation Count: 9
Film Formation of Nano-Sized Hard Latex (PS) in Soft Polymer Matrix (PBA): An Excimer Study
(John Wiley & Sons Inc, 2010) Uğur, Şaziye; Sunay, Selin; Pekcan, Önder
This work reports steady state fluorescence (SSF) technique for studying film formation from pyrene (P)labeled nano-sized polystyrene (PS) and poly(n-butyl acrylate) (PBA) hard/soft latex blends. Blend films were prepared from mixtures of PS and PBA in dispersion. Eight different blend films were prepared in various hard/soft latex compositions at room temperature and annealed at elevated temperatures above glass transition temperature (T(g)) of polystyerene. Monomer (I(P)) and excimer (I(E)) intensities from P was measured after each annealing step to monitor the stages of film formation. The evolution of transparency of latex films was monitored using photon transmission intensity I(tr). Film morphologies were examined by atomic force microscopy (AFM). The results showed that as the amount of hard component (PS) in the blend is decreased a significant change occurred in both I(E)/I(P) and I(tr) curves at a certain critical weight fraction (50 wt%) of PS hard latex. Two distinct film formation stages which are named as void closure and interdiffusion were seen in (I(E)/I(P)) data above this fraction. However below 50 wt% PS no film formation was observed. AFM pictures also confirmed these findings. Void closure and interdiffusion stages for (50-100) wt% range of PS were modeled and related activation energies were determined. There was no observable change in activation energies confirming that film formation behavior is not affected by varying the blend composition in this range. POLYM. COMPOS. 31:16111619 2010. (C) 2009 Society of Plastics Engineers
Citation Count: 2
Film Formation of Poly (methyl methacrylate) Latex With Pyrene Functional Poly (divinylbenzene) Microspheres Prepared by Click Chemistry
(Wiley-Blackwell, 2011) Uğur, Şaziye; Yargı, Önder; Durmaz, Yasemin Yuksel; Karagöz, Bünyamin; Bıçak, Niyazi; Yağci, Yusuf; Pekcan, Önder; Pekcan, Önder
This work reports on the application of steady state fluorescence (SSF) technique for studying film formation from poly(methyl methacrylate) (PMMA) latex and poly(divinylbenzene) (PDVB) microsphere composites. Pyrene (P) functionalized PDVB cross-linked spherical microspheres with diameters of 2.5 mu m were synthesized by using precipitation polymerization technique followed by click coupling reaction. The diameter of the PMMA particles prepared by emulsion polymerization were in the range of 0.5-0.7 mu m. PMMA/PDVB composite films were then prepared by physically blending of PMMA latex with PDVB microspheres at various composition (0 1 3 5 10 20 40 and 60 wt%). After drying films were annealed at elevated temperatures above T(g) of PMMA ranging from 100 to 270 degrees C for 10 min time intervals. Evolution of transparency of the composite films was monitored by using photon transmission intensity I(tr). Monomer (I(P)) and excimer (I(E)) fluorescence intensities from P were measured after each annealing step. The possibility of using the excimer-to-monomer intensity ratio (I(E)/I(P)) from PDVB microparticles as a measure of PMMA latex coalescence was demonstrated. Diffusion of the PMMA chains across the particle-particle interfaces dilutes the dyes increasing their separation. The film formation stages of PMMA latexes were modeled by monitoring the I(E)/I(P) ratios and related activation energies were determined. There was no observable change in activation energies confirming that film formation behavior is not affected by varying the PDVB composition in the studied range. SEM images of PMMA/PDVB composites confirmed that the PMMA particles undergo complete coalescence forming a continuous phase in where PDVB microspheres are dispersed. POLYM. COMPOS. 32: 869-881 2011. (C) 2011 Society of Plastics Engineers
Citation Count: 26
Flavonoids from Sideritis Species: Human Monoamine Oxidase (hMAO) Inhibitory Activities Molecular Docking Studies and Crystal Structure of Xanthomicrol
(MDPI, 2015) Yelekçi, Kemal; Baysal, Ipek; Çiftçi-Yabanoğlu, Samiye; Yelekçi, Kemal; Temel, Hamdi; Paşa, Salih; Ezer, Nurten; Çalış, Ihsan; Uçar, Gülberk
The inhibitory effects of flavonoids on monoamine oxidases (MAOs) have attracted great interest since alterations in monoaminergic transmission are reported to be related to neurodegenerative diseases such as Parkinson's and Alzheimer's diseases and psychiatric disorders such as depression and anxiety thus MAOs may be considered as targets for the treatment of these multi-factorial diseases. In the present study four Sideritis flavonoids xanthomicrol (1) isoscutellarein 7-O-[6'''-O-acetyl--d-allopyranosyl-(12)]--d-glucopyranoside (2) isoscutellarein 7-O-[6'''-O-acetyl--d-allopyranosyl-(12)]-6''-O-acetyl--d-glucopyranoside (3) and salvigenin (4) were docked computationally into the active site of the human monoamine oxidase isoforms (hMAO-A and hMAO-B) and were also investigated for their hMAO inhibitory potencies using recombinant hMAO isoenzymes. The flavonoids inhibited hMAO-A selectively and reversibly in a competitive mode. Salvigenin (4) was found to be the most potent hMAO-A inhibitor while xanthomicrol (1) appeared as the most selective hMAO-A inhibitor. The computationally obtained results were in good agreement with the corresponding experimental values. In addition the x-ray structure of xanthomicrol (1) has been shown. The current work warrants further preclinical studies to assess the potential of xanthomicrol (1) and salvigenin (4) as new selective and reversible hMAO-A inhibitors for the treatment of depression and anxiety.
Citation Count: 4
Fluorescence quenching method for monitoring oxygen diffusion into PS/CNT composite films
(Elsevier Science SA, 2013) Yargı, Önder; Uğur, Şaziye; Pekcan, Önder
Oxygen permeabilities of nanocomposite films consisting of multi wall carbon nanotubes (MWNT) and polystyrene (PS) were determined to investigate the oxygen diffusion depending on MWNT and temperature. A method which is based on quenching of an excited phosphorescent by oxygen was applied for the measurements. The composite films were prepared from mixtures of (MWNT) and surfactant-free pyrene (P)-labeled (PS) latexes of various compositions at room temperature. These films were then annealed at 170 degrees C which is well above the glass transition (T-g) temperature of polystyrene for 10 min. Diffusion experiments were performed for eight films with different MWNT content (0 1.5 3 5 10 15 25 and 40 wt%) to evaluate the effect of MWNT content on oxygen diffusion. Diffusion coefficients were found to increase from 1.1 x 10(-12) to 41 x 10(-12) cm(2) s(-1) with increasing MWNT content. On the other hand to examine the effect of temperature on oxygen diffusion diffusion measurements were performed over a temperature range of 24-70 degrees C for three different MWNT contents (3 15 and 40 wt%) within the films. The results indicated that the values of the diffusion coefficient D are strongly dependent on both temperature and MWNT content in the film. It was also observed that the diffusion coefficients obey Arrhenius behavior from which diffusion energies were determined which increased with increase of MWNT content and temperature. (C) 2013 Elsevier B.V. All rights reserved.
Citation Count: 1
Fluorescence study of film formation from PS/Al2O3 nanocomposites
(Elsevier Science, 2014) Pekcan, Önder; Uğur, Şaziye; Sunay, M. Selin
Steady state fluorescence (SSF) and UV-vis (UVV) techniques were used to study the film formation behavior of pyrene (P) labeled polystyrene (PS) latex and Al2O3 (PS/Al2O3) composites depending on PS particles size and Al2O3 content. The close-packed arrays of PS spheres (SmPS: 203 nm ; LgPS: 382 nm) templates on clean glass substrates were covered with various layers of Al2O3 by dip-coating method. Two different film series (SmPS/Al2O3 and LgPS/Al2O3) were prepared in various Al2O3 layer content. The film formation behavior of these composites were studied by annealing them at a temperature range of 100-250 degrees C and monitoring the scattered light intensity (I-sc) fluorescence intensity (I-p) from P and transmitted light intensity (I-tr) through the films after each annealing step. Optical results indicate that classical latex film formation was occurred for all Al2O3 content films and film formation process was unaffected by the Al2O3 content for both film series. Extraction of PS template produced highly ordered porous structures for high Al2O3 content in both film series. SEM images showed that the pore size and porosity could be easily tailored by varying the PS particle size and the Al2O3 content. (C) 2014 Elsevier B.V. All rights reserved.
Citation Count: 3
Fractal dimension and phase transition of graphene oxide (GO) doped polyacrylamide
(ELSEVIER SCI LTD, 2020) Evingür, Gülşen Akın; Pekcan, Önder
Graphene Oxide (GO)- Polyacrylamide composites prepared between 5 and 50 mu l GO were performed by Fluorescence Spectroscopy. The phase transition performed on the composites was measured by calculating the critical exponents, beta and gamma, respectively. In addition, fractal analysis of the composites was calculated by a fluorescence intensity of 427 nm. The geometrical distribution of GO in the composites was calculated based on the power law exponent values using scaling models. While the gelation proceeded GO plates first organized themselves into a 3D percolation cluster with the fractal dimension (D-f) of the composite, D-f = 2.63, then After it goes to diffusion limited clusters with D-f = 1.4, its dimension lines up to a Von Koch curve with a random interval of D-f = 1.14.
Citation Count: 1
Group behaviour in physical chemical and biological systems
(Indıan Acad Scıences, 2014) Saçlıoğlu, Cihan; Pekcan, Önder; Nanjundiah, Vidyanand
Groups exhibit properties that either are not perceived to exist or perhaps cannot exist at the individual level. Such 'emergent' properties depend on how individuals interact both among themselves and with their surroundings. The world of everyday objects consists of material entities. These are ultimately groups of elementary particles that organize themselves into atoms and molecules occupy space and so on. It turns out that an explanation of even the most commonplace features of this world requires relativistic quantum field theory and the fact that Planck's constant is discrete not zero. Groups of molecules in solution in particular polymers ('sols') can form viscous clusters that behave like elastic solids ('gels'). Sol-gel transitions are examples of cooperative phenomena. Their occurrence is explained by modelling the statistics of inter-unit interactions: the likelihood of either state varies sharply as a critical parameter crosses a threshold value. Group behaviour among cells or organisms is often heritable and therefore can evolve. This permits an additional typically biological explanation for it in terms of reproductive advantage whether of the individual or of the group. There is no general agreement on the appropriate explanatory framework for understanding group-level phenomena in biology.
Citation Count: 10
Holocene climate forcings and lacustrine regime shifts in the Indian summer monsoon realm
(Wıley, 2020) Eroğlu, Deniz; Marwan, Norbert; Eroğlu, Deniz; Goswami, Bedartha; Mishra, Praveen Kuma; Gaye, Birgit; Anoop, Akhil; Stebich, Martina; Jehangir, Arshid; Basavaiah, Nathani
Extreme climate events have been identified both in meteorological and long-term proxy records from the Indian summer monsoon (ISM) realm. However, the potential of palaeoclimate data for understanding mechanisms triggering climate extremes over long time scales has not been fully exploited. A distinction between proxies indicating climate change, environment, and ecosystem shift is crucial for enabling a comparison with forcing mechanisms (e.g. El-Nino Southern Oscillation). In this study we decouple these factors using data analysis techniques [multiplex recurrence network (MRN) and principal component analyses (PCA)] on multiproxy data from two lakes located in different climate regions - Lonar Lake (ISM dominated) and the high-altitude Tso Moriri Lake (ISM and westerlies influenced). Our results indicate that (i) MRN analysis, an indicator of changing environmental conditions, is associated with droughts in regions with a single climate driver but provides ambiguous results in regions with multiple climate/environmental drivers; (ii) the lacustrine ecosystem was 'less sensitive' to forcings during the early Holocene wetter periods; (iii) archives in climate zones with a single climate driver were most sensitive to regime shifts; (iv) data analyses are successful in identifying the timing of onset of climate change, and distinguishing between extrinsic and intrinsic (lacustrine) regime shifts by comparison with forcing mechanisms. Our results enable development of conceptual models to explain links between forcings and regional climate change that can be tested in climate models to provide an improved understanding of the ISM dynamics and their impact on ecosystems. (c) 2020 John Wiley & Sons, Ltd.
Citation Count: 24
How an Inhibitor Bound to Subunit Interface Alters Triosephosphate Isomerase Dynamics
(Cell Press, 2015) Akdoğan, Ebru Demet; Fındık, Doğa; Akdoğan, Ebru Demet; Doruker, Pemra
The tunnel region at triosephosphate isomerase (TIM)'s dimer interface distant from its catalytic site is a target site for certain benzothiazole derivatives that inhibit TIM's catalytic activity in Trypanosoma cruzi the parasite that causes Chagas disease. We performed multiple 100-ns molecular-dynamics (MD) simulations and elastic network modeling (ENM) on both apo and complex structures to shed light on the still unclear inhibitory mechanism of one such inhibitor named bt10. Within the time frame of our MD simulations we observed stabilization of aromatic clusters at the dimer interface and enhancement of intersubunit hydrogen bonds in the presence of bt10 which point to an allosteric effect rather than destabilization of the dimeric structure. The collective dynamics dictated by the topology of TIM is known to facilitate the closure of its catalytic loop over the active site that is critical for substrate entrance and product release. We incorporated the ligand's effect on vibrational dynamics by applying mixed coarse-grained ENM to each one of 54000 MD snapshots. Using this computationally efficient technique we observed altered collective modes and positive shifts in eigenvalues due to the constraining effect of bt10 binding. Accordingly we observed allosteric changes in the catalytic loop's dynamics flexibility and correlations as well as the solvent exposure of catalytic residues. A newly (to our knowledge) introduced technique that performs residue-based ENM scanning of TIM revealed the tunnel region as a key binding site that can alter global dynamics of the enzyme.
Citation Count: 15
Identification of Alternative Allosteric Sites in Glycolytic Enzymes for Potential Use as Species-Specific Drug Targets
(Frontiers Media, 2020) Ayyıldız, Merve; Çeliker, Serkan; Özhelvacı, Fatih; Akten, Ebru Demet
Three allosteric glycolytic enzymes, phosphofructokinase, glyceraldehyde-3 phosphate dehydrogenase and pyruvate kinase, associated with bacterial, parasitic and human species, were explored to identify potential allosteric sites that would be used as prime targets for species-specific drug design purposes using a newly developed approach which incorporates solvent mapping, elastic network modeling, sequence and structural alignments. The majority of binding sites detected by solvent mapping overlapped with the interface regions connecting the subunits, thus appeared as promising target sites for allosteric regulation. Each binding site was then evaluated by its ability to alter the global dynamics of the receptor defined by the percentage change in the frequencies of the lowest-frequency modes most significantly and as anticipated, the most effective ones were detected in the vicinity of the well-reported catalytic and allosteric sites. Furthermore, some of our proposed regions intersected with experimentally resolved sites which are known to be critical for activity regulation, which further validated our approach. Despite the high degree of structural conservation encountered between bacterial/parasitic and human glycolytic enzymes, the majority of the newly presented allosteric sites exhibited a low degree of sequence conservation which further increased their likelihood to be used as species-specific target regions for drug design studies.
Citation Count: 13
In situ steady state fluorescence (SSF) technique to study drying of PAAm hydrogels made of various cross-linker contents
(Elsevier Science, 2009) Evingür, Gülşen Akın; Aktas, Demet Kaya; Pekcan, Önder
Drying experiments of polyacrylamide (PAAm) gels were performed using steady-state fluorescence (SSF) spectrometer. Pyranine (P) was introduced as a fluorescence probe and intensity of P from various crosslinker content gel samples was monitored. It was observed that the intensity of P increased during the in situ drying processes. Gravimetrical and volumetric experiments were also performed. An empirical model was derived and introduced to determine the desorption coefficient D of water molecules from the drying PAAm gels. It is observed that D increased as the cross-linker content was increased. (c) 2008 Elsevier B.V. All rights reserved.

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