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Publication Metadata only A computational model for controlling conformational cooperativity and function in proteins(Wiley, 2018) Department of Chemical and Biological Engineering; Erman, Burak; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 179997We present a computational model that allows for rapid prediction of correlations among a set of residue pairs when the fluctuations of another set of residues are perturbed. The simple theory presented here is based on the knowledge of the fluctuation covariance matrix only. In this sense, the theory is model independent and therefore universal. Perturbation of any set of fluctuations and the resulting response of the remaining set are calculated using conditional probabilities of a multivariate normal distribution. The model is expected to rapidly and accurately map the consequences of mutations in proteins, as well as allosteric activity and ligand binding. Knowledge of triple correlations of fluctuations of residues i, j, and k, 〈ΔRiΔRjΔRk〉 emerges as the necessary source of information for controlling residue pairs by perturbing a distant residue. Triple correlations have not received wide attention in literature. Perturbation–response–function relations for ubiquitin (UBQ) are discussed as an example. Covariance matrix for UBQ obtained from the Gaussian Network Model combined with the present computational algorithm is able to reflect the millisecond molecular dynamics correlations and observed NMR results.Publication Metadata only A fast approximate method of identifying paths of allosteric communication in proteins(Wiley, 2013) Department of Chemical and Biological Engineering; Erman, Burak; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 179997Fluctuations of the distance between a pair of residues i and j may be correlated with the fluctuations of the distance between another pair k and l. In this case, information may be transmitted among these four residues. Allosteric activity is postulated to proceed through such correlated paths. In this short communication a fast method for calculating correlations among all possible pairs ij and kl leading to a pathway of correlated residues of a protein is proposed. The method is based on the alpha carbon centered Gaussian Network Model. The model is applied to Glutamine Amidotransferase and pathways of allosteric activity are identified and compared with literature. Proteins 2013; 81:1097-1101. (c) 2013 Wiley Periodicals, Inc.Publication Metadata only A molecular dynamics study of allosteric transitions in Leishmania mexicana pyruvate kinase(Cell Press, 2015) Naithani, Ankita; Taylor, Paul; Walkinshaw, Malcolm D.; Department of Chemical and Biological Engineering; Erman, Burak; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 179997A comparative molecular dynamics analysis of the pyruvate kinase from Leishmania mexicana is presented in the absence and presence of the allosteric effector fructose 2,6-bisphosphate. Comparisons of the simulations of the large 240 kDa apo and holo tetramers show that binding of fructose 2,6-bisphosphate cools the enzyme and reduces dynamic movement, particularly of the B-domain. The reduced dynamic movement of the holo form traps the pyruvate kinase tetramer in its enzymatically active state with the B-domain acting as a lid to cover the active site. The simulations are also consistent with a transition of the mobile active-site alpha 6' helix, which would adopt a helical conformation in the active R-state and a less structured coil conformation in the inactive T-state. Analysis of the rigid body motions over the trajectory highlights the concerted anticorrelated rigid body rocking motion of the four protomers, which drives the T to R transition. The transitions predicted by these simulations are largely consistent with the Monod-Wyman-Changeux model for allosteric activation but also suggest that rigidification or cooling of the overall structure upon effector binding plays an additional role in enzyme activation.Publication Metadata only A new dataset of non-redundant protein/protein interfaces(Biophysical Society, 2003) Tsai, CJ; Wolfson, H; Nussinov, R; Department of Chemical and Biological Engineering; Keskin, Özlem; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 26605Publication Metadata only A new dataset of protein-protein interfaces(Cell Press, 2007) Güney, Emre; Nussinov, Ruth; Tsai, C. J.; Department of Computer Engineering; Department of Chemical and Biological Engineering; Gürsoy, Attila; Keskin, Özlem; Tunçbağ, Nurcan; Faculty Member; Faculty Member; PhD Student; Department of Computer Engineering; Department of Chemical and Biological Engineering; College of Engineering; College of Engineering; 8745; 26605; 245513Publication Metadata only A structural view of negative regulation of the toll-like receptor-mediated inflammatory pathway(Cell Press, 2015) Gursoy, Attila; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Maiorov, Emine Güven; Keskin, Özlem; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; The Center for Computational Biology and Bioinformatics (CCBB); Graduate School of Sciences and Engineering; College of Engineering; N/A; 26605Even though the Toll-like receptor (TLR) pathway is integral to inflammatory defense mechanisms, its excessive signaling may be devastating. Cells have acquired a cascade of strategies to regulate TLR signaling by targeting protein-protein interactions, or ubiquitin chains, but the details of the inhibition mechanisms are still unclear. Here, we provide the structural basis for the regulation of TLR signaling by constructing architectures of protein-protein interactions. Structural data suggest that 1) Toll/IL-1R (TIR) domain-containing regulators (BCAP, SIGIRR, and ST2) interfere with TIR domain signalosome formation; 2) major deubiquitinases such as A20, CYLD, and DUBA prevent association of TRAF6 and TRAF3 with their partners, in addition to removing K63-linked ubiquitin chains that serve as a docking platform for downstream effectors; 3) alternative downstream pathways of TLRs also restrict signaling by competing to bind common partners through shared binding sites. We also performed in silico mutagenesis analysis to characterize the effects of oncogenic mutations on the negative regulators and to observe the cellular outcome (whether there is/is not inflammation). Missense mutations that fall on interfaces and nonsense/frameshift mutations that result in truncated negative regulators disrupt the interactions with the targets, thereby enabling constitutive activation of the nuclear factor-kappa B, and contributing to chronic inflammation, autoimmune diseases, and oncogenesis.Publication Metadata only An all-aqueous approach for physical immobilization of PEG-lipid microgels on organoid surfaces(Elsevier, 2020) N/A; N/A; Department of Chemical and Biological Engineering; Akolpoğlu, Mükrime Birgül; İnceoğlu, Yasemin; Kızılel, Seda; Master Student; Master Student; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; N/A; 28376Emulsion-based generation of hydrogel particles has been widely explored for numerous applications in fields such as biomedical, food, and drug delivery. Water-in-water emulsion (w/w) is an organic solvent-free approach and exploits solely aqueous media to generate nano- or micropartides. This strategy is environment-friendly and favorable for biomedical applications where biocompatibility is the ultimate criterion. Hence, PEG-based microgels can be synthesized with desired size and functionality using w/w emulsion technique. To estimate the influence of emulsification parameters on size and stability of PEG-lipid microgels, optimizations using three independent input variables were carried out: (i) ultrasonication power, (ii) ultrasonication duration, and (iii) duration of light exposure. Physical immobilization of microgels on islet-organoids was achieved through hydrophobic interactions. Cell function and viability were assessed thoroughly after microgel immobilization. Microgel size is dependent on ultrasonication parameters and microgel stability is vastly determined by the duration of light exposure. Immobilization of microgels with 5 mM lipid moiety promoted coating of islet-organoids. Coated organoids retained their function and viability without significant adverse effects. This is important for understanding fundamental aspects of PEG-lipid microgels using w/w emulsion, useful for possible drug/gene delivery applications to increase treatment efficiency and ultimately lead to clinical translation of PEG microgels for biomedical applications.Publication Metadata only Analysis and network representation of hotspots in protein interfaces using minimum cut trees(Wiley, 2010) Department of Chemical and Biological Engineering; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Tunçbağ, Nurcan; Salman, Fatma Sibel; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; College of Engineering; College of Engineering; College of Engineering; College of Engineering; 245513; 178838; 26605; 8745We propose a novel approach to analyze and visualize residue contact networks of protein interfaces by graph-based algorithms using a minimum cut tree (mincut tree). Edges in the network are weighted according to an energy function derived from knowledge-based potentials. The mincut tree, which is constructed from the weighted residue network, simplifies and summarizes the complex structure of the contact network by an efficient and informative representation. This representation offers a comprehensible view of critical residues and facilitates the inspection of their organization. We observed, on a nonredundant data set of 38 protein complexes with experimental hotspots that the highest degree node in the mincut tree usually corresponds to an experimental hotspot. Further, hotspots are found in a few paths in the mincut tree. In addition, we examine the organization of hotspots (hot regions) using an iterative clustering algorithm on two different case studies. We find that distinct hot regions are located on specific sites of the mincut tree and some critical residues hold these clusters together. Clustering of the interface residues provides information about the relation of hot regions with each other. Our new approach is useful at the molecular level for both identification of critical paths in the protein interfaces and extraction of hot regions by clustering of the interface residues.Publication Metadata only Anharmonicity, mode-coupling and entropy in a fluctuating native protein(Iop Publishing Ltd, 2010) N/A; Department of Physics; Department of Computer Engineering; N/A; Department of Chemical and Biological Engineering; Kabakçıoğlu, Alkan; Yüret, Deniz; Gür, Mert; Erman, Burak; Faculty Member; Faculty Member; PhD Student; Faculty Member; Department of Physics; Department of Computer Engineering; Department of Chemical and Biological Engineering; College of Sciences; College of Engineering; Graduate School of Sciences and Engineering; College of Engineering; 49854; 179996; 216930; 179997We develop a general framework for the analysis of residue fluctuations that simultaneously incorporates anharmonicity and mode-coupling in a unified formalism. We show that both deviations from the Gaussian model are important for modeling the multidimensional energy landscape of the protein Crambin (1EJG) in the vicinity of its native state. the effect of anharmonicity and mode-coupling on the fluctuational entropy is in the order of a few percent.Publication Metadata only Attenuation of Type IV pili activity by natural products(Taylor & Francis Inc, 2024) Yalkut, Kerem; Hassine, Soumaya Ben Ali; Kula, Ceyda; Ozcan, Aslihan; Avci, Fatma Gizem; Akbulut, Berna Sariyar; Ozbek, Pemra; Department of Chemical and Biological Engineering; Başaran, Esra; Keskin, Özlem; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of EngineeringThe virulence factor Type IV pili (T4P) are surface appendages used by the opportunistic pathogen Pseudomonas aeruginosa for twitching motility and adhesion in the environment and during infection. Additionally, the use of these appendages by P. aeruginosa for biofilm formation increases its virulence and drug resistance. Therefore, attenuation of the activity of T4P would be desirable to control P. aeruginosa infections. Here, a computational approach has been pursued to screen natural products that can be used for this purpose. PilB, the elongation ATPase of the T4P machinery in P. aeruginosa, has been selected as the target subunit and virtual screening of FDA-approved drugs has been conducted. Screening identified two natural compounds, ergoloid and irinotecan, as potential candidates for inhibiting this T4P-associated ATPase in P. aeruginosa. These candidate compounds underwent further rigorous evaluation through molecular dynamics (MD) simulations and then through in vitro twitching motility and biofilm inhibition assays. Notably, ergoloid emerged as a particularly promising candidate for weakening the T4P activity by inhibiting the elongation ATPases associated with T4P. This repurposing study paves the way for the timely discovery of antivirulence drugs as an alternative to classical antibiotic treatments to help combat infections caused by P. aeruginosa and related pathogens.