Biyoinformatik ve Genetik Bölümü Koleksiyonu
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Article Citation Count: 7Antifungal screening and in silico mechanistic studies of an in-house azole library(2019) Sarı, Suat; Kart, Didem; Sabuncuoğlu, Suna; Doğan, İnci Selin; Özdemir, Zeynep; Bozbey, İrem; Gencel, Melis; Eşsiz, Şebnem; Reynisson, Jóhannes; Karakurt, Arzu; Saraç, Selma; Dalkara, SevimSystemic Candida infections pose a serious public health problem with high morbidity and mortality. C. albicans is the major pathogen identified in candidiasis; however, non-albicans Candida spp. with antifungal resistance are now more prevalent. Azoles are first-choice antifungal drugs for candidiasis; however, they are ineffective for certain infections caused by the resistant strains. Azoles block ergosterol synthesis by inhibiting fungal CYP51, which leads to disruption of fungal membrane permeability. In this study, we screened for antifungal activity of an in-house azole library of 65 compounds to identify hit matter followed by a molecular modeling study for their CYP51 inhibition mechanism. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed derivatives 12 and 13 as highly active. Furthermore, they showed potent antibiofilm activity as well as neglectable cytotoxicity in a mouse fibroblast assay. According to molecular docking studies, 12 and 13 have the necessary binding characteristics for effective inhibition of CYP51. Finally, molecular dynamics simulations of the C. albicans CYP51 (CACYP51) homology model's catalytic site complexed with 13 were stable demonstrating excellent binding.Article Citation Count: 2Aryl butenoic acid derivatives as a new class of histone deacetylase inhibitors: synthesis in vitro evaluation and molecular docking studies(Scientific Technical Research Council Turkey-Tubitak, 2014) Yelekçi, Kemal; Seven, özlem; Eymur, Guluzar; Tatar, Gamze Bora; Erden, Didem Dayangaç; Yelekçi, Kemal; Yurter, Hayat; Demir, Ayhan S.New aryl butenoic acid derivatives have been synthesized by combining hydroxy- or methoxy-substituted phenyl rings as the capping group with a double bond in the short linker as well as metal binding groups enoic ester and salts bearing either methyl or morpholine. These compounds have been shown to possess promising histone deacetylase inhibition activities via in vitro fluorometric assay and molecular docking studies.Conference Object Citation Count: 0Atomic collisions and free lepton pair production(2005) Güçlü, Mehmet Cem; Yılmaz, MelekIn this work we have calculated the total cross sections of electron-positron pair production for the collisions of fully stripped gold ions for various energies. We have also compared our calculation with other methods.Article Citation Count: 0Classification Of Distinct Conformers Of Beta < 2-Adrenergic Receptor (Beta 2-AR) Based On Binding Affinity Of Ligands Through Docking Studies(Amer Chemical Soc, 2016) Akten, Ebru Demet; Dilcan, GoncaB2AR reseptörü, akciğerlerin rahatlamasında ve kardiyovasküler fizyolojide rol oynamasıyla önemli bir ilaç hedefidir. Bu çalışmada, çeşitli B2AR konformasyonlarını aktif veya inaktif olarak sınıflandırmak amacıyla, aktivitesi bilinen ligantlar seçilerek onların bağlanma şekillerine göre bir sınıflandırma stratejisi oluşturulmuştur. Önceki bir çalışmada gerçekleştirilen, reseptörün inaktif halinin 2.8 μs'lik MD simülasyonunda, ligandın bağlanma bölgesinin farklı konformasyonları elde edilmiştir. Snapshotlar derlenerek bağlanma bölgesindeki beş anahtar rezidünün RMSD değerlerine göre gruplandırılmıştır. Toplamda 13 farklı konformasyon elde edilmiş ve 5 agonist, 4 ters agonist ve 4 antagonist molekülü her bir konformasyona ayrı ayrı ve 7 farklı skor fonksiyonu kullanılarak dock edilmiştir. En iyi yerleşen konformasyonlar bağlanma bölgesindeki anahtar rezidülerle olan yakınlığına göre seçilmiş ve hesaplanmıştır. Anahtar bölgeye yaklaşamayanlar elenmiş, kalanlar ise skor değerlerine göre sıralanmıştır. Bu sınıflandırma, kritik değerlendirme yapabilmek için MD konformasyonlarından önce aktivitesi bilinen aktif/inaktif kristal yapılara uygulanmıştır. Her skor fonksiyonu tarafından seçilen ve ilk 5'te bulunan MD konformasyonları aktif ve inaktif olarak sınıflandırılmıştır. Son olarak, MD konformasyonlarının ayırt ediciliğini analiz edebilmek için, seçilen bu konformasyonlar ile küçük bir dataset kullanılarak sanal tarama yapılmıştır. MD konformasyonlarının inaktif kristal yapıya göre antagonist/ters agonistler için daha seçici olduğu gözlemlenmiştir. Reseptörün alternatif konformasyonlarını üretmek ve onları sınıflandırmak, genellikle tek bir snaphot X-ray örneği ile sınırlandırılmış ilaç tasarımı çalışmalarında önemli rol oynamaktadır.Conference Object Citation Count: 0Collective enhancement of nuclear state densities by the shell model Monte Carlo approach(IOP Publishing Ltd, 2015) Özen, Cem; Alhassid, Yoram; Nakada, HitoshiThe shell model Monte Carlo (SMMC) approach allows for the microscopic calculation of statistical and collective properties of heavy nuclei using the framework of the configuration-interaction shell model in very large model spaces. We present recent applications of the SMMC method to the calculation of state densities and their collective enhancement factors in rare-earth nuclei.Conference Object Citation Count: 1Collectivity in Heavy Nuclei in the Shell Model Monte Carlo Approach(EDP Sciences, 2014) Özen, Cem; Alhassid, Yoram; Nakada, HitoshiThe microscopic description of collectivity in heavy nuclei in the framework of the configuration-interaction shell model has been a major challenge. The size of the model space required for the description of heavy nuclei prohibits the use of conventional diagonalization methods. We have overcome this difficulty by using the shell model Monte Carlo (SMMC) method which can treat model spaces that are many orders of magnitude larger than those that can be treated by conventional methods. We identify a thermal observable that can distinguish between vibrational and rotational collectivity and use it to describe the crossover from vibrational to rotational collectivity in families of even-even rare-earth isotopes. We calculate the state densities in these nuclei and find them to be in close agreement with experimental data. We also calculate the collective enhancement factors of the corresponding level densities and find that their decay with excitation energy is correlated with the pairing and shape phase transitions.Conference Object Citation Count: 0COMP 297-Experimental and molecular docking simulation studies of Histone deacetylases (HDACs) enzyme inhibitors(Amer Chemical Soc, 2007) Yelekçi, Kemal; Bora, Gamze; Dayangaç-Erden, Didem; Ayhan, Peruze; Dalkara, Sevim; Demir, Ayhan S.; Erdem-Yurter, Hayat[Abstract Not Available]Article Citation Count: 5Computational Analysis of a Zn-Bound Tris(imidazolyl) Calix[6]arene Aqua Complex: Toward Incorporating Second-Coordination Sphere Effects into Carbonic Anhydrase Biomimetics(Amer Chemical Soc, 2013) Eşsiz, Şebnem; Eşsiz, Şebnem; Wong, Sergio E.; Lau, Edmond Y.; Valdez, Carlos A.; Satcher, Joe H. Jr.; Aines, Roger D.; Lightstone, Felice C.Molecular dynamics simulations and quantum-mechanical calculations were performed to characterize a supra-molecular tris(imidazolyl) calix[6]arene Zn2+ aqua complex as a biomimetic model for the catalyzed hydration of carbon dioxide to bicarbonate H2O + CO2 -> H+ + HCO3-. On the basis of potential-of-mean-force (PMF) calculations stable conformations had distorted 3-fold symmetry and supported either one or zero encapsulated water molecules. The conformation with an encapsulated water molecule is calculated to be lower in free energy than the conformation with an empty cavity (Delta G = 1.2 kcal/mol) and is the calculated free-energy minimum in solution. CO2 molecule partitioning into the cavity is shown to be very facile proceeding with a barrier of 1.6 kcal/mol from a weak encounter complex which stabilizes the species by about 1.0 kcal/mol. The stabilization energy of CO2 is calculated to be larger than that of H2O (Delta Delta G = 1.4 kcal/mol) suggesting that the complex will preferentially encapsulate CO2 in solution. In contrast the PMF for a bicarbonate anion entering the cavity is calculated to be repulsive in all nonbonding regions of the cavity due to the diameter of the calix[6]arene walls. Geometry optimization of the Zn-bound hydroxide complex with an encapsulated CO2 molecule showed that multiple noncovalent interactions direct the reactants into optimal position for nucleophilic addition to occur. The calixarene complex is a structural mimic of the hydrophilic/hydrophobic divide in the enzyme providing a functional effect for CO2 addition in the catalytic cycle. The results show that Zn-binding calix[6]arene scaffolds can be potential synthetic biomimetics for CO2 hydration catalysis both in terms of preferentially encapsulating CO2 from solution and by spatially fixing the reactive species inside the cavity.Book Part Citation Count: 2Conductivity Percolation of Carbon Nanotubes in Polyacrylamide Gels(Intech Europe, 2011) Pekcan, Önder; Evingür, Gülşen Akın[Abstract Not Available]Article Citation Count: 44Crossover from Vibrational to Rotational Collectivity in Heavy Nuclei in the Shell-Model Monte Carlo Approach(Amer Physical Soc., 2013) Özen, Cem; Alhassid, Yoram; Nakada, HitoshiHeavy nuclei exhibit a crossover from vibrational to rotational collectivity as the number of neutrons or protons increases from shell closure towards midshell but the microscopic description of this crossover has been a major challenge. We apply the shell model Monte Carlo approach to families of even-even samarium and neodymium isotopes and identify a microscopic signature of the crossover from vibrational to rotational collectivity in the low-temperature behavior of < J(2)>(T) where J is the total spin and T is the temperature. This signature agrees well with its values extracted from experimental data. We also calculate the state densities of these nuclei and find them to be in very good agreement with experimental data. Finally we define a collective enhancement factor from the ratio of the total state density to the intrinsic state density as calculated in the finite-temperature Hartree-Fock-Bogoliubov approximation. The decay of this enhancement factor with excitation energy is found to correlate with the pairing and shape phase transitions in these nuclei. DOI: 10.1103/PhysRevLett.110.042502Article Citation Count: 14Crystallographic structure versus homology model: a case study of molecular dynamics simulation of human and zebrafish histone deacetylase 10(Taylor & Francis, 2020) Yelekçi, Kemal; Yelekçi, KemalHistone deacetylase (HDAC) 10 has been implicated in the pathology of various cancers and neurodegenerative disorders, making the discovery of novel inhibitors of the isoform an important endeavor. However, the unavailability of crystallographic structure of human HDAC10 (hHDAC10) hinders structure-based drug design effort. Previously, we reported the homology modeled structure of human HDAC10 built using the crystallographic structure of Danio rerio (zebrafish) HDAC10 (zHDAC10) (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) as a template. Here, in continuation with our study, both hHDAC10 and zHDAC10, and their respective complexes with trichostatin A (TSA), quisinostat, and the native ligand (in 5TD7), 7-[(3-aminopropyl)amino]-1,1,1-trifluoroheptane-2,2-diol (PDB ID; FKS) were submitted to 100 ns-long unrestrained molecular dynamics (MD) simulations. Comparative analyses of the MD trajectories revealed that zHDAC10 and its complexes displayed higher stability than hHDAC10 and its corresponding complexes over time. Nonetheless, docking of active and inactive set molecules revealed that more reliable conformations of hHDAC10 could be obtained at an extended time period. This study may shed more light on the reliability of hHDAC10 modeled structure for use in selective inhibitor design.Communicated by Ramaswamy H. Sarma.Article Citation Count: 6The design of potent HIV-1 integrase inhibitors by a combined approach of structure-based virtual screening and molecular dynamics simulation(Taylor & Francis Ltd, 2018) Yelekçi, Kemal; Yelekçi, Kemal; Uba, Abdullahi IbrahimBu araştırmanın amacı, AIDS olarak bilinen insan bağışıklık sistemine etki eden, duraksamayan ve depresif bir hastalığa neden olan HIV-1'in tedavisi için potansiyel inhibitörleri elde etmektir. HIV-1 integraz inhibitörleri, HIV-1 enfeksiyonunun tedavisinde çok önemlidir. İntegraz enziminin (IN) inhibe edilmesi HIV-1 virüsünün çoğalma işleminin sonlandırılmasına neden olur. Böylece yaşam döngüsüne son verir. Bu inhibitörleri elde etmek için bilgisayar destekli in silico yaklaşım kullanılmıştır. Temelde, Otava Kimya Kütüphanesi tarandı ve inhibitör tasarımında kullanılan sistematik yaklaşımlar uygulandı, böylece dört güçlü integraz inhibitörü bulundu. İnhibitörlerin enzime bağlanma değerleri PyRx ve AutoDock 4.2 doklama programları kullanılarak gerçekleştirildi. Çalışmada bir kimyasalın güçlü bir inhibitör olabilmesi için hesaplanan serbest bağ enerjisi = -8.00 kcal / mol veya daha az olması ve integrazın aktif bölgesinde bulunan 3 önemli amino asidinden herhangi biri ile de etkileşimde bulunması kriterine uyulmuştur. Discovery Studio Visualizer, inhibitörlerin yapısını çizmekte, inhibitörü komplekslerinin resimlerini üretmekte, enzim ve inhibitör arasındaki etkileşimin türünü belirlememizi sağlayan 2D ve 3D yapıları görüntülemek için kullanıldı. Elde edilen dört güçlü inhibitörden, kendimizin tasarladığı moleküllerden (Ki= 652.83 nanomolar bir ve bağlanma serbest enerjisi -8.44kcal / mol), kalan üç inhibitörde, Otava Kimya Kütüphanesi'nde tarandı ve Otava koduyla parantez içerisinde listelenmiştir. Bunların inhibisyon sabiti ve bağlanma enerjileri sırasıyla; 107320240, Ki=131.7nm, -9.39kcal/ mol; 109750115, Ki= 44.19nm, -10.03kcal / mol; 111150115 Ki = 395.19nm, -8.74kcal / mol olarak bulunmuştur.Article Citation Count: 0Determination of growth kinetics and size dependent structural morphological optical characteristics of sol-gel derived silica nanoparticles in silica matrix(De Gruyter Poland Sp Zoo, 2019) Uysal, Bengü Özuğur; Tepehan, Fatma ZehraNanocomposite silica thin films made using the sol-gel method were studied. The nano-silica films were prepared using a mixture of tetraethyl orthosilicate (TEOS) deionized water ethanol and ammonia solution. To control the growth of the particles inside the film the nanocomposite silica film was prepared using a mixture of the nano-silica sol and the silica sol. The change in the particle size with the heat treatment temperature ranging from 450 degrees C to 1100 degrees C was investigated. X-ray diffraction (XRD) atomic force microscopy (AFM) scanning electron microscopy (SEM) NKD (refractive index-N extinction coefficient-K and thickness-D) and ultraviolet-visible (UV-Vis) spectrophotometry were used for characterization purposes. The XRD studies showed that the nano-silica thin films were amorphous at all annealing temperatures except for 1100 degrees C. The alpha-cristobalite crystal structure formed at the annealing temperature of 1100 degrees C. Optical parameters such as refractive indices and extinction coefficients were obtained using the NKD analyzer with respect to the annealing temperature of the films. The activation energy and enthalpy of the nanocomposite silica film were evaluated as 22.3 kJ/mol and 14.7 kJ/mol respectively. The cut-off wavelength values were calculated by means of extrapolation of the absorbance spectra estimated using the UV-Vis spectroscopy measurements. A red shift in the absorption threshold of the nanocomposite silica films indicated that the size of the silica nanoparticles increased with an increase of the annealing temperatures from 450 degrees C to 900 degrees C and this confirms the quantum confinement effect in the nanoparticles.Article Citation Count: 20The Drosophila fragile X mental retardation protein participates in the piRNA pathway(Company of Biologists Ltd, 2015) Bozzetti, Maria Pia; Specchia, Valeria; Cattenoz, Pierre B.; Laneve, Pietro; Geusa, Annamaria; Şahin, H. Bahar; Di Tommaso, Silvia D.; Friscini, Antonella; Massari, Serafina; Diebold, Celine; Giangrande, AngelaRNA metabolism controls multiple biological processes and a specific class of small RNAs called piRNAs act as genome guardians by silencing the expression of transposons and repetitive sequences in the gonads. Defects in the piRNA pathway affect genome integrity and fertility. The possible implications in physiopathological mechanisms of human diseases have made the piRNA pathway the object of intense investigation and recent work suggests that there is a role for this pathway in somatic processes including synaptic plasticity. The RNA-binding fragile X mental retardation protein (FMRP also known as FMR1) controls translation and its loss triggers the most frequent syndromic form of mental retardation as well as gonadal defects in humans. Here we demonstrate for the first time that germline as well as somatic expression of Drosophila Fmr1 (denoted dFmr1) the Drosophila ortholog of FMRP are necessary in a pathway mediated by piRNAs. Moreover dFmr1 interacts genetically and biochemically with Aubergine an Argonaute protein and a key player in this pathway. Our data provide novel perspectives for understanding the phenotypes observed in Fragile X patients and support the view that piRNAs might be at work in the nervous system. © 2015.Article Citation Count: 6Drying of Polyacrylamide Composite Gels Formed with Various Kappa- Carrageenan Content(Springer/Plenum Publishers, 2011) Evingür, Gülşen Akın; Pekcan, ÖnderDrying of polyacrylamide (PAAm)-kappa-carrageenan (kappa C) composite gels were monitored by using steady-state fluorescence technique. Disc shaped gels were formed from acrylamide (AAm) and N N'- methylenebisacrylamide(Bis) with various kappa- carrageenan (kappa C) contents by free radical crosslinking copolymerization in water. Pyranine (P) was doped as a fluorescence probe and scattered light I (sc) and fluorescence intensities I were monitored during drying of these gels. It is observed that fluorescence intensity of pyranine increased as drying time is increased for all samples. The increase in I was modeled using Stern- Volmer equation and diffusion with moving boundary. It is found that desorption coefficient D decreased as kappa C contents were increased. Supporting gravimetrical and volumetric experiments were also carried out during drying of PAAm- kappa C composite gels.Article Citation Count: 4Drying of polyacrylamide-multiwalled carbon nanotube (MWNT) composites with various MWNTs contents: a fluorescence study(Walter De Gruyter Gmbh, 2013) Evingür, Gülşen Akin; Pekcan, ÖnderWe studied the drying of polyacrylamide (PAAm)-multiwalled carbon nanotube (MWNT) composites prepared by free radical crosslinking copolymerization in water with a steady state fluorescence technique. Composite gels were prepared at room temperature with pyranine (Py) doped as a fluorescence probe. Drying experiments were performed in air at various MWNT contents by real time monitoring of the Py fluorescence intensity (I) which increased as the drying proceeded. The Stern-Volmer equation combined with the moving boundary diffusion model was used to explain the behavior of I during drying. It was observed that the desorption coefficient (D) increased as the temperature increased. Drying energies (Delta E) were measured for the drying processes for each MWNT content gel by using fluorescence gravimetrical and volumetric methods. It is understood that Delta E values decrease by increasing MWNT content until 1 wt % MWNT and then increase above the level of this threshold value. The energy of drying is strongly correlated with the MWNT content in the composite. Delta E drops to its lowest value at which conducting cluster starts to appear.Article Citation Count: 0Drying process in vapor swollen heterogels(Springer, 2010) Erdogan, Matem; Pekcan, ÖnderDisk-shaped heterogels were prepared by combining methyl methacrylate (MMA) and styrene (S) with ethylene glycol dimethacrylate (EGDM) as a crosslinker agent in the presence of 22'-azobisisobutyronitrile (AIBN). Swelling experiments were performed under chloroform vapor and the swollen gels are then allowed to dry under room temperature. Gravimetric technique was used to study drying processes. It is observed that two different regimes are present in the drying processes of these heterogels. Fickian diffusion model was used to determine desorption coefficients for each drying step in both regimes. Desorption coefficients D (d) of heterogels were found to be strongly correlated with the mixture composition of polymeric materials in the heterogel system for both regimes. Heterogels with high S content dry much slower than the heterogels with low S content.Book Part Citation Count: 0EFFECT OF CONTENT AND TEMPERATURE ON THE PHASE TRANSITIONS OF POLYMER COMPOSITES DOPED BY KAPPA CARRAGEENAN AND ALGINATE(Elsevier Academic Press Inc, 2016) Evingür, Gülşen Akın; Pekcan, Önder[Abstract Not Available]Article Citation Count: 3The effect of film thickness and TiO2 content on film formation from PS/TiO2 nanocomposites prepared by dip-coating method(Hindawi Publishing Corporation, 2012) Sunay, M. Selin; Pekcan, Önder; Ugur, SaziyeSteady-state fluorescence (SSF) technique in conjunction with UV-visible (UVV) technique and atomic force microscope (AFM) was used for studying film formation from TiO2 covered nanosized polystyrene (PS) latex particles (320 nm). The effects of film thickness and TiO2 content on the film formation and structure properties of PS/TiO2 composites were studied. For this purpose two different sets of PS films with thicknesses of 5 and 20 mu m were prepared from pyrene-(P-) labeled PS particles and covered with various layers of TiO2 using dip-coating method. These films were then annealed at elevated temperatures above glass transition temperature (T-g) of PS in the range of 100-280 degrees C. Fluorescence emission intensity I-p from P and transmitted light intensity I-tr were measured after each annealing step to monitor the stages of film formation. The results showed that film formation from PS latexes occurs on the top surface of PS/TiO2 composites and thus developed independent of TiO2 content for both film sets. But the surface morphology of the films was found to vary with both TiO2 content and film thickness. After removal of PS thin films provide a quite ordered porous structure while thick films showed nonporous structure.Article Citation Count: 28Effect of intracellular loop 3 on intrinsic dynamics of human 2-adrenergic receptor(Bmc, 2013) Ozcan, Ozer; Uyar, Arzu; Doruker, Pemra; Akten, Ebru DemetBackground: To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human beta(2)-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 mu s molecular dynamics (MD) simulation at 310 K. Results: After around 600 ns, the loop model started a transition to a very inactive conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein's binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 angstrom from 11 angstrom, which was further elaborated by docking studies. Conclusions: The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the very inactive state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes.