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Now showing 1 - 5 of 5
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    PublicationOpen Access
    Non-redundant unique interface structures as templates for modeling protein interactions
    (Public Library of Science, 2014) Nussinov, Ruth; (TBD); Gürsoy, Attila; Çukuroğlu, Engin; Keskin, Özlem; Faculty Member; PhD Student; (TBD); The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; 8745; N/A; 26605
    Improvements in experimental techniques increasingly provide structural data relating to protein-protein interactions. Classification of structural details of protein-protein interactions can provide valuable insights for modeling and abstracting design principles. Here, we aim to cluster protein-protein interactions by their interface structures, and to exploit these clusters to obtain and study shared and distinct protein binding sites. We find that there are 22604 unique interface structures in the PDB. These unique interfaces, which provide a rich resource of structural data of protein-protein interactions, can be used for template-based docking. We test the specificity of these non-redundant unique interface structures by finding protein pairs which have multiple binding sites. We suggest that residues with more than 40% relative accessible surface area should be considered as surface residues in template-based docking studies. This comprehensive study of protein interface structures can serve as a resource for the community. The dataset can be accessed at https://prism.ccbb.ku.edu.tr/piface.
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    PublicationOpen 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 Medicine
    It 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.
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    PublicationOpen Access
    The structural pathway of interleukin 1 (IL-1) initiated signaling reveals mechanisms of oncogenic mutations and SNPs in inflammation and cancer
    (Public Library of Science, 2014) Nussinov, Ruth; (TBD); Gürsoy, Attila; Özbabacan, Saliha Ece Acuner; Keskin, Özlem; Faculty Member; (TBD); The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; 8745; N/A; 26605
    Structural pathways are important because they provide insight into signaling mechanisms; help understand the mechanism of disease-related mutations; and help in drug discovery. While extremely useful, common pathway diagrams lacking structural data are unable to provide mechanistic insight to explain oncogenic mutations or SNPs. Here we focus on the construction of the IL-1 structural pathway and map oncogenic mutations and SNPs to complexes in this pathway. Our results indicate that computational modeling of protein-protein interactions on a large scale can provide accurate, structural atom-level detail of signaling pathways in the human cell and help delineate the mechanism through which a mutation leads to disease. We show that the mutations either thwart the interactions, activating the proteins even in their absence or stabilize them, leading to the same uncontrolled outcome. Computational mapping of mutations on the interface of the predicted complexes may constitute an effective strategy to explain the mechanisms of mutations- constitutive activation or deactivation.
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    PublicationMetadata only
    Towards inferring time dimensionality in protein-protein interaction networks by integrating structures: the p53 example
    (Royal Society of Chemistry (RSC), 2009) Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Computer Engineering; (TBD); N/A; Keskin, Özlem; Gürsoy, Attila; Tunçbağ, Nurcan; Makinacı, Gözde Kar; Faculty Member; Faculty Member; Faculty Member; PhD Student; Department of Chemical and Biological Engineering; Department of Computer Engineering; (TBD); The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; College of Engineering; College of Engineering; Graduate School of Sciences and Engineering; 26605; 8745; 245513; N/A
    Inspection of protein-protein interaction maps illustrates that a hub protein can interact with a very large number of proteins, reaching tens and even hundreds. Since a single protein cannot interact with such a large number of partners at the same time, this presents a challenge: can we figure out which interactions can occur simultaneously and which are mutually excluded? Addressing this question adds a fourth dimension into interaction maps: that of time. Including the time dimension in structural networks is an immense asset; time dimensionality transforms network node-and-edge maps into cellular processes, assisting in the comprehension of cellular pathways and their regulation. While the time dimensionality can be further enhanced by linking protein complexes to time series of mRNA expression data, current robust, network experimental data are lacking. Here we outline how, using structural data, efficient structural comparison algorithms and appropriate datasets and filters can assist in getting an insight into time dimensionality in interaction networks; in predicting which interactions can and cannot co-exist; and in obtaining concrete predictions consistent with experiment. As an example, we present p53-linked processes.
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    PublicationOpen Access
    Unified modeling of familial mediterranean fever and cryopyrin associated periodic syndromes
    (Hindawi, 2015) Bozkurt, Yasemin; Gül, Ahmet; (TBD); (TBD); Demir, Alper; Erman, Burak; Faculty Member; Faculty Member; (TBD); Graduate School of Sciences and Engineering; College of Engineering; 3756; 179997
    Familial mediterranean fever (FMF) and Cryopyrin associated periodic syndromes (CAPS) are two prototypical hereditary autoinflammatory diseases, characterized by recurrent episodes of fever and inflammation as a result of mutations in MEFV and NLRP3 genes encoding Pyrin and Cryopyrin proteins, respectively. Pyrin and Cryopyrin play key roles in the multiprotein inflammasome complex assembly, which regulates activity of an enzyme, Caspase 1, and its target cytokine, IL-1 beta. Overproduction of IL-1 beta by Caspase 1 is the main cause of episodic fever and inflammatory findings in FMF and CAPS. We present a unifying dynamical model for FMF and CAPS in the form of coupled nonlinear ordinary differential equations. The model is composed of two subsystems, which capture the interactions and dynamics of the key molecular players and the insults on the immune system. One of the subsystems, which contains a coupled positive-negative feedback motif, captures the dynamics of inflammation formation and regulation. We perform a comprehensive bifurcation analysis of the model and show that it exhibits three modes, capturing the Healthy, FMF, and CAPS cases. The mutations in Pyrin and Cryopyrin are reflected in the values of three parameters in the model. We present extensive simulation results for the model that match clinical observations.