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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access The structural basis of Akt PH domain interaction with calmodulin(Elsevier, 2021) Jang, Hyunbum; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Weako, Jackson; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 26605; 8745Akt plays a key role in the Ras/PI3K/Akt/mTOR signaling pathway. In breast cancer, Akt translocation to the plasma membrane is enabled by the interaction of its pleckstrin homology domain (PHD) with calmodulin (CaM). At the membrane, the conformational change promoted by PIP3 releases CaM and facilitates Thr308 and Ser473 phosphorylation and activation. Here, using modeling and molecular dynamics simulations, we aim to figure out how CaM interacts with Akt's PHD at the atomic level. Our simulations show that CaM-PHD interaction is thermodynamically stable and involves a beta-strand rather than an alpha-helix, in agreement with NMR data, and that electrostatic and hydrophobic interactions are critical. The PHD interacts with CaM lobes; however, multiple modes are possible. IP4, the polar head of PIP3, weakens the CaM-PHD interaction, implicating the release mechanism at the plasma membrane. Recently, we unraveled the mechanism of PI3K alpha activation at the atomistic level and the structural basis for Ras role in the activation. Here, our atomistic structural data clarify the mechanism of how CaM interacts, delivers, and releases Akt-the next node in the Ras/PI3K pathway-at the plasma membrane.Publication Open Access In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials(Taylor _ Francis, 2020) Asar, Sinan; Okyar, Alper; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Gül, Şeref; Özcan, Onur; Barış, İbrahim; Kavaklı, İbrahim Halil; Researcher; Teaching Faculty; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; N/A; N/A; 111629; 40319Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CL(pro)) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CL(pro)based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients.Publication Open Access Understanding formation and structure of peptide nanofibers via steered MD simulations(Elsevier, 2012) Department of Mechanical Engineering; Engin, Özge; Özgür, Beytullah; Sayar, Mehmet; PhD Student; Faculty Member; Department of Mechanical Engineering; College of Engineering; N/A; N/A; 109820Publication Open Access PRISM-EM: template interface-based modelling of multi-protein complexes guided by cryo-electron microscopy density maps (corrigendum)(International Union of Crystallography, 2018) Nussinov, Ruth; Department of Chemical and Biological Engineering; Kuzu, Güray; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; N/A; 26605; 8745A revised Table 6 and Supporting Information are provided for the article by Kuzu et al. [(2016 ), Acta Cryst. D72, 1137-1148].Publication Open Access Binding induced conformational changes of proteins correlate with their intrinsic fluctuations: a case study of antibodies(BioMed Central, 2007) Keskin, Özlem; Faculty Member; Faculty Member; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; 26605Background: How antibodies recognize and bind to antigens can not be totally explained by rigid shape and electrostatic complimentarity models. Alternatively, pre- existing equilibrium hypothesis states that the native state of an antibody is not defined by a single rigid conformation but instead with an ensemble of similar conformations that co-exist at equilibrium. Antigens bind to one of the preferred conformations making this conformation more abundant shifting the equilibrium. Results: Here, two antibodies, a germline antibody of 36 - 65 Fab and a monoclonal antibody, SPE7 are studied in detail to elucidate the mechanism of antibody-antigen recognition and to understand how a single antibody recognizes different antigens. An elastic network model, Anisotropic Network Model (ANM) is used in the calculations. Pre- existing equilibrium is not restricted to apply to antibodies. Intrinsic fluctuations of eight proteins, from different classes of proteins, such as enzymes, binding and transport proteins are investigated to test the suitability of the method. The intrinsic fluctuations are compared with the experimentally observed ligand induced conformational changes of these proteins. The results show that the intrinsic fluctuations obtained by theoretical methods correlate with structural changes observed when a ligand is bound to the protein. The decomposition of the total fluctuations serves to identify the different individual modes of motion, ranging from the most cooperative ones involving the overall structure, to the most localized ones. Conclusion: Results suggest that the pre- equilibrium concept holds for antibodies and the promiscuity of antibodies can also be explained this hypothesis: a limited number of conformational states driven by intrinsic motions of an antibody might be adequate to bind to different antigens.Publication Open Access Transition from the fetal to neonatal circulation: Modeling the effects of umbilical cord clamping(Elsevier, 2015) Yiğit, Mehmet B.; Kowalski, William J.; Hutchon, David J.R.; Department of Mechanical Engineering; Pekkan, Kerem; Faculty Member; Department of Mechanical Engineering; College of Engineering; 161845Hemodynamics of the fetal to neonatal transition are orchestrated through complex physiological changes and results in cardiovascular adaptation to the adult biventricular circulation. Clinical practice during this critical period can influence vital organ physiology for normal newborns, premature babies and congenital heart defect patients. Particularly, the timing of the cord clamping procedure, immediate (ICC) vs. delayed cord clamping (DCC), is hypothesized to be an important factor for the transitory fetal hemodynamics. The clinical need for a quantitative understanding of this physiology motivated the development of a lumped parameter model (LPM) of the fetal cardio-respiratory system covering the late-gestation to neonatal period. The LPM was validated with in vivo clinical data and then used to predict the effects of cord clamping procedures on hemodynamics and vital gases. Clinical time-dependent resistance functions to simulate the vascular changes were introduced. For DCC, placental transfusion (31.3ml) increased neonatal blood volume by 11.7%. This increased blood volume is reflected in an increase in preload pressures by ~20% compared to ICC, which in turn increased the cardiac output (CO) by 20% (CO.sub.ICC =993ml/min; CO.sub.DCC =1197ml/min). Our model accurately predicted dynamic flow patterns in vivo. DCC was shown to maintain oxygenation if the onset of pulmonary respiration was delayed or impaired. On the other hand, a significant 25% decrease in oxygen saturations was observed when applying ICC under the same physiological conditions. We conclude that DCC has a significant impact on newborn hemodynamics, mainly because of the improved blood volume and the sustained placental respiration.Publication Open Access The photolyase/cryptochrome family of proteins as DNA repair enzymes and transcriptional repressors(Wiley, 2017) Aydın, Cihan; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Kavaklı, İbrahim Halil; Barış, İbrahim; Tardu, Mehmet; Gül, Şeref; Öner, Haşimcan; Bulut, Selma; Yarparvar, Darya; Ustaoğlu, Pınar; Teaching Faculty; PhD Student; Researcher; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; College of Engineering; College of Sciences; 40319; 111629; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/ALight is a very important environmental factor that governs many cellular responses in organisms. As a consequence, organisms possess different kinds of light-sensing photoreceptors to regulate their physiological variables and adapt to a given habitat. The cryptochrome/photolyase family (CPF) includes photoreceptors that perform different functions in different organisms. Photolyases repair ultraviolet-induced DNA damage by a process known as photoreactivation using photons absorbed from the blue end of the light spectrum. On the other hand, cryptochromes act as blue light circadian photoreceptors in plants and Drosophila to regulate growth and development. In mammals, cryptochromes have light-independent functions and are very important transcriptional regulators that act at the molecular level as negative transcriptional regulators of the circadian clock. In this review, we highlight current knowledge concerning the structural and functional relationships of CPF members.Publication Open Access Significant variations in Weber fraction for changes in inter-onset interval of a click train over the range of intervals between 5 ms and 300 ms(Frontiers, 2014) Yağcıoğlu, Süha; (TBD); Ungan, Pekcan; Faculty Member; (TBD); School of MedicineIt is a common psychophysical experience that a train of clicks faster than ca. 30/s is heard as one steady sound, whereas temporal patterns occurring on a slower time scale are perceptually resolved as individual auditory events. This phenomenon suggests the existence of two different neural mechanisms for processing of auditory sequences with fast and slow repetition rates. To test this hypothesis we used Weber's law, which is known to be valid for perception of time intervals. Discrimination thresholds and Weber fractions (WFs) for 12 base inter click intervals (ICIs) between 5 and 300 ms were measured from 10 normal hearing subjects by using an ""up-down staircase"" algorithm. The mean WE which is supposed to be constant for any perceptual mechanism according to Weber's law, displayed significant variation with click rate. WFs decreased sharply from an average value of around 5% at repetition rates below 20 Hz to about 0.5% at rates above 67 Hz. Parallel to this steep transition, subjects reported that at rates below 20 Hz they perceived periodicity as a fast tapping rhythm, whereas at rates above 50 Hz the perceived quality was a pitch. Such a dramatic change in WE indicated the existence of two separate mechanisms for processing the click rate for long and short ICIs, based on temporal and spectral features, respectively. A range of rates between 20 and 33 Hz, in which the rate discrimination threshold was maximum, appears to be a region where both of the presumed time and pitch mechanisms are relatively insensitive to rate alterations. Based on this finding, we speculate that the interval-based perception mechanism ceases to function at around 20 Hz and the spectrum based mechanism takes over at around 33 Hz; leaving a transitional gap in between, where neither of the two mechanisms is as sensitive. Another notable finding was a significant drop in WE for ICI = 100 ms, suggesting a connection of time perception to the electroencephalography alpha rhythm.Publication Open Access Causality, transfer entropy, and allosteric communication landscapes in proteins with harmonic interactions(Wiley, 2017) Department of Chemical and Biological Engineering; Hacısüleyman, Aysima; Erman, Burak; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; N/A; 179997A fast and approximate method of generating allosteric communication landscapes in proteins is presented by using Schreiber's entropy transfer concept in combination with the Gaussian Network Model of proteins. Predictions of the model and the allosteric communication landscapes generated show that information transfer in proteins does not necessarily take place along a single path, but an ensemble of pathways is possible. The model emphasizes that knowledge of entropy only is not sufficient for determining allosteric communication and additional information based on time delayed correlations should be introduced, which leads to the presence of causality in proteins. The model provides a simple tool for mapping entropy sink-source relations into pairs of residues. By this approach, residues that should be manipulated to control protein activity may be determined. This should be of great importance for allosteric drug design and for understanding the effects of mutations on function. The model is applied to determine allosteric communication in three proteins, Ubiquitin, Pyruvate Kinase, and the PDZ domain. Predictions are in agreement with molecular dynamics simulations and experimental evidence.Publication Open Access ModiBodies: a computational method for modifying nanobodies in nanobody-antigen complexes to improve binding affinity and specificity(Springer, 2020) Department of Chemical and Biological Engineering; Hacısüleyman, Aysima; Erman, Burak; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 179997Nanobodies are special derivatives of antibodies, which consist of single domain fragments. They have become of considerable interest as next-generation biotechnological tools for antigen recognition. They can be easily engineered due to their high stability and compact size. Nanobodies have three complementarity-determining regions, CDRs, which are enlarged to provide a similar binding surface to that of human immunoglobulins. Here, we propose a benchmark testing algorithm that uses 3D structures of already existing protein-nanobody complexes as initial structures followed by successive mutations on the CDR domains. The aim is to find optimum binding amino acids for hypervariable residues of CDRs. We use molecular dynamics simulations to compare the binding energies of the resulting complexes with that of the known complex and accept those that are improved by mutations. We use the MDM4-VH9 complex, (PDB id 2VYR), fructose-bisphosphate aldolase from Trypanosoma congolense (PDB id 5O0W) and human lysozyme (PDB id 4I0C) as benchmark complexes. By using this algorithm, better binding nanobodies can be generated in a short amount of time. We suggest that this method can complement existing immune and synthetic library-based methods, without a need for extensive experimentation or large libraries.