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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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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 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.Publication Open Access Gaussian network model revisited: effects of mutation and ligand binding on protein behavior(Institute of Physics (IOP) Publishing, 2022) Department of Chemical and Biological Engineering; Erman, Burak; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 179997The coarse-grained Gaussian network model (GNM), considers only the alpha carbons of the folded protein. Therefore it is not directly applicable to the study of mutation or ligand binding problems where atomic detail is required. This shortcoming is improved by including all atom pairs within the coordination shell of each other into the Kirchoff adjacency matrix. Counting all contacts rather than only alpha carbon contacts diminishes the magnitude of fluctuations in the system. But more importantly, it changes the graph-like connectivity structure, i.e., the Kirchoff adjacency matrix of the protein. This change depends on amino acid type which introduces amino acid specific and position specific information into the classical coarse-grained GNM which was originally modeled in analogy with the phantom network model of rubber elasticity. With this modification, it is now possible to explain the consequences of mutation and ligand binding on residue fluctuations, their pair-correlations and mutual information shared by each pair. We refer to the new model as 'all-atom GNM'. Using examples from published data we show that the all-atom GNM gives B-factors that are in better agreement with experiment, can explain effects of mutation on long range communication in PDZ domains and can predict effects of GDP and GTP binding on the dimerization of KRAS.Publication Open Access Comparing interfacial dynamics in protein-protein complexes: an elastic network approach(BioMed Central, 2010) Zen, Andrea; Micheletti, Cristian; Nussinov, Ruth; Keskin, Özlem; Faculty Member; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; 26605Background: The transient, or permanent, association of proteins to form organized complexes is one of the most common mechanisms of regulation of biological processes. Systematic physico-chemical studies of the binding interfaces have previously shown that a key mechanism for the formation/stabilization of dimers is the steric and chemical complementarity of the two semi-interfaces. The role of the fluctuation dynamics at the interface of the interacting subunits, although expectedly important, proved more elusive to characterize. The aim of the present computational study is to gain insight into salient dynamics-based aspects of protein-protein interfaces. Results: The interface dynamics was characterized by means of an elastic network model for 22 representative dimers covering three main interface types. The three groups gather dimers sharing the same interface but with good (type I) or poor (type II) similarity of the overall fold, or dimers sharing only one of the semi-interfaces (type III). The set comprises obligate dimers, which are complexes for which no structural representative of the free form (s) is available. Considerations were accordingly limited to bound and unbound forms of the monomeric subunits of the dimers. We proceeded by first computing the mobility of amino acids at the interface of the bound forms and compare it with the mobility of (i) other surface amino acids (ii) interface amino acids in the unbound forms. In both cases different dynamic patterns were observed across interface types and depending on whether the interface belongs to an obligate or non-obligate complex. Conclusions: The comparative investigation indicated that the mobility of amino acids at the dimeric interface is generally lower than for other amino acids at the protein surface. The change in interfacial mobility upon removing "in silico" the partner monomer (unbound form) was next found to be correlated with the interface type, size and obligate nature of the complex. In particular, going from the unbound to the bound forms, the interfacial mobility is noticeably reduced for dimers with type I interfaces, while it is largely unchanged for type II ones. The results suggest that these structurally-and biologically-different types of interfaces are stabilized by different balancing mechanisms between enthalpy and conformational entropy.Publication Open Access Cloning, expression, purification, crystallization and X-ray analysis of inositol monophosphatase from Mus musculus and Homo sapiens(Wiley, 2012) Singh, Nisha; Halliday, Amy C.; Knight, Matthew; Lowe, Edward; Churchill, Grant C.; Lack, Nathan Alan; Faculty Member; School of Medicine; 120842Inositol monophosphatase (IMPase) catalyses the hydrolysis of inositol monophosphate to inositol and is crucial in the phosphatidylinositol (PI) signalling pathway. Lithium, which is the drug of choice for bipolar disorder, inhibits IMPase at therapeutically relevant plasma concentrations. Both mouse IMPase 1 (MmIMPase 1) and human IMPase 1 (HsIMPase 1) were cloned into pRSET5a, expressed in Escherichia coli, purified and crystallized using the sitting-drop method. The structures were solved at resolutions of 2.4 and 1.7 angstrom, respectively. Comparison of MmIMPase 1 and HsIMPase 1 revealed a core r.m.s. deviation of 0.516 angstrom.