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Publication Metadata only A computational biomechanical investigation of posterior dynamic instrumentation: combination of dynamic rod and hinged (dynamic) screw(Asme, 2014) Kiapour, Ali; Goel, Vijay K.; N/A; N/A; Erbulut, Deniz Ufuk; Öktenoğlu, Bekir Tunç; Özer, Ali Fahir; Researcher; Faculty Member; School of Medicine, College of Engineering; School of Medicine; 37661; 220898; 1022Currently, rigid fixation systems are the gold standard for degenerative disk disease treatment. Dynamic fixation systems have been proposed as alternatives for the treatment of a variety of spinal disorders. These systems address the main drawbacks of traditional rigid fixation systems, such as adjacent segment degeneration and instrumentation failure. Pedicle-screw-based dynamic stabilization (PDS) is one type of these alternative systems. The aim of this study was to simulate the biomechanical effect of a novel posterior dynamic stabilization system, which is comprised of dynamic (hinged) screws interconnected with a coiled, spring-based dynamic rod (DSDR), and compare it to semirigid (DSRR and RSRR) and rigid stabilization (RSRR) systems. A validated finite element (FE) model of L1-S1 was used to quantify the biomechanical parameters of the spine, such as range of motion, intradiskal pressure, stresses and facet loads after single-level instrumentation with different posterior stabilization systems. The results obtained from in vitro experimental intact and instrumented spines were used to validate the FE model, and the validated model was then used to compare the biomechanical effects of different fixation and stabilization constructs with intact under a hybrid loading protocol. The segmental motion at L4-L5 increased by 9.5% and 16.3% in flexion and left rotation, respectively, in DSDR with respect to the intact spine, whereas it was reduced by 6.4% and 10.9% in extension and left-bending loads, respectively. After instrumentation-induced intradiskal pressure at adjacent segments, L3-L4 and L5-S1 became less than the intact in dynamic rod constructs (DSDR and RSDR) except in the RSDR model in extension where the motion was higher than intact by 9.7% at L3-L4 and 11.3% at L5-S1. The facet loads were insignificant, not exceeding 12N in any of the instrumented cases in flexion. In extension, the facet load in DSDR case was similar to that in intact spine. The dynamic rod constructions (DSDR and RSDR) led to a lesser peak stress at screws compared with rigid rod constructions (DSRR and RSRR) in all loading cases. A dynamic construct consisting of a dynamic rod and a dynamic screw did protect the adjacent level from excessive motion.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 mixed basis with off-center Gaussian functions for the calculation of the potential energy surfaces for pi-stacking interactions: dimers of benzene and planar C-6(Springer, 2015) Department of Chemistry; Yurtsever, İsmail Ersin; Faculty Member; Department of Chemistry; College of Sciences; 7129A practical mixed basis set was developed to facilitate accurate calculations of potential energy surfaces for pi-stacking interactions. Correlation consistent basis sets (cc-PVXZ) were augmented by p-type Gaussian functions placed above and below the planes of C-6 moieties. Moller-Plesset (MP2, SCS-MP2) and coupled cluster [CCSD(T)] calculations show that such generated basis sets provide an accurate description of p-stacking systems with favorable computation times compared to the standard augmented basis sets. The addition of these off-center functions eliminates the linear dependence of the augmented basis sets, which is one of the most encountered numerical problems during calculation of the oligomers of polyaromatic hydrocarbons (PAH). In this work, we present a comparative study of the general characteristics of the potential energy surfaces for the parallel stacked and T-shape conformations of benzene and planar C6 clusters, using a combination of cc-PVXZ and our optimized functions. We discuss properties, such as the depth and curvature of the potential functions, short and long distance behavior, and the frictional forces between two model monomers.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 post-HF study on the interaction of iodine with small polyaromatic hydrocarbons(Springer, 2014) Sutay, Berkay; Yurtsever, Mine; Department of Chemistry; Yurtsever, İsmail Ersin; Faculty Member; Department of Chemistry; College of Sciences; 7129In this work, we present a theoretical study of the interaction between a diatomic iodine molecule with planar naphthalene and several other small polyaromatic hydrocarbons (PAHs). Our aim was to understand the general characteristics of the potential energy surface (PES) of this system; that is locating various local minima, finding the variation of PES around these optimum points by means of first principle calculations at MP2, SCS-MP2 and CCSD(T) levels of theory. Two basic orientations of the iodine molecule, i.e., parallel or perpendicular with respect to the naphthalene plane, are discussed. The PES of the former was investigated in detail, including the translation and rotation of I-2 (as a rigid rotor) along the naphtalene surface. It was concluded that, although the perpendicular conformations are usually 1 kcal mol(-1) more stable than the parallel conformation, this small difference does not exclude the presence of both conformations in the gas phase. Both structures were stable enough to hold more than 20 vibrational states. NBO analysis showed that the mutual polarization effects were greater for the perpendicular conformation. It was also observed that the I-2+naphtalene dimer interaction is almost twice of that of I-2+naphtalene, showing the long range character of the interaction.Publication 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 An ultra-compact and wireless tag for battery-free sweat glucose monitoring(Elsevier Advanced Technology, 2022) N/A; Department of Mechanical Engineering; N/A; N/A; Department of Mechanical Engineering; N/A; N/A; N/A; N/A; Department of Mechanical Engineering; Mirzajani, Hadi; Abbasiasl, Taher; Mirlou, Fariborz; İstif, Emin; Bathaei, Mohammad Javad; Dağ, Çağdaş; Deyneli, Oğuzhan; Dereli, Dilek Yazıcı; Beker, Levent; Researcher; PhD Student; PhD Student; Other; PhD Student; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Department of Mechanical Engineering; Koç Üniversitesi İş Bankası Enfeksiyon Hastalıkları Uygulama ve Araştırma Merkezi (EHAM) / Koç University İşbank Center for Infectious Diseases (KU-IS CID); n2STAR-Koç University Nanofabrication and Nanocharacterization Center for Scientifc and Technological Advanced Research; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; Graduate School of Sciences and Engineering; N/A; School of Medicine; School of Medicine; College of Engineering; N/A; N/A; N/A; N/A; N/A; N/A; 171914; 179659; 308798Glucose monitoring before, during, and after exercise is essential for people with diabetes as exercise increases the risk of activity-induced hyper- and hypo-glycemic events. The situation is even more challenging for athletes with diabetes as they have impaired metabolic control compared to sedentary individuals. In this regard, a compact and noninvasive wearable glucose monitoring device that can be easily worn is critical to enabling glucose monitoring. This report presents an ultra-compact glucose tag with a footprint and weight of 1.2 cm(2) and 0.13 g, respectively, for sweat analysis. The device comprises a near field communication (NFC) chip, antenna, electrochemical sensor, and microfluidic channels implemented in different material layers. The device has a flexible and conformal structure and can be easily attached to different body parts. The battery-less operation of the device was enabled by NFC-based wireless power transmission and the compact antenna. Femtosecond laser ablation was employed to fabricate a highly compact and flexible NFC antenna. The proposed device demonstrated excellent operating characteristics with a limit of detection (LOD), limit of quantification (LOQ), and sensitivity of 24 mu M, 74 mu M, and 1.27 mu A cm(-2) mM(-1), respectively. The response of the proposed sensor in sweat glucose detection and quantification was validated by nuclear magnetic resonance spectroscopy (NMR). Also, the device's capability in attachment to the body, sweat collection, and glucose measurement was demonstrated through in vitro and in vivo experiments, and satisfactory results were obtained.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.