Publications with Fulltext
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; Department of Chemical and Biological Engineering; Department of Computer Engineering; Weako, Jackson; Keskin, Özlem; Gürsoy, Attila; Faculty Member; 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 Interlaced: fully decentralized churn stabilization for Skip Graph-based DHTs(Elsevier, 2021) Department of Computer Engineering; Department of Computer Engineering; Hassanzadeh-Nazarabadi, Yahya; Küpçü, Alptekin; Özkasap, Öznur; PhD Student; Faculty Member; Graduate School of Sciences and Engineering; College of Engineering; N/A; 168060; 113507As a distributed hash table (DHT) routing overlay, Skip Graph is used in a variety of peer-to-peer (P2P) systems including cloud storage. The overlay connectivity of P2P systems is negatively affected by the arrivals and departures of nodes to and from the system that is known as churn. Preserving connectivity of the overlay network (i.e., the reachability of every pair of nodes) under churn without compromising the overlay latency is a performance challenge in every P2P system including the Skip Graph-based ones. The existing decentralized churn stabilization solutions that are applicable to Skip Graphs mainly optimize the connectivity of the system under churn and do not consider routing latency of overlay as an optimization goal. Additionally, those existing solutions change the message complexity of Skip Graphs, distort its topology, or apply constant message overhead to the system. In this paper, we propose Interlaced, a fully decentralized churn stabilization mechanism for Skip Graphs that provides drastically stronger overlay connectivity and faster search queries without changing the asymptotic complexity of the Skip Graph in terms of storage, computation, and communication. We also propose the Sliding Window De Bruijn Graph (SWDBG ) as a tool to predict the availability of nodes with high accuracy. Our simulation results show that in comparison to the best existing DHT-based solutions, Interlaced improves the overlay connectivity of the Skip Graph under churn with the gain of about 1.73 times. Likewise, compared to the existing availability prediction approaches for P2P systems, SWDBG is about 1.26 times more accurate. A Skip Graph that benefits from Interlaced and SWDBG is about 2.47 times faster on average in routing the queries under churn compared to the best existing solutions. We also present an adaptive extension of Interlaced to be applied to other DHTs, for example, Kademlia.Publication Open Access Multiple shape correspondence by dynamic programming(Wiley, 2014) Sahillioğlu, Y.; Department of Computer Engineering; Department of Computer Engineering; Yemez, Yücel; Faculty Member; College of EngineeringWe present a multiple shape correspondence method based on dynamic programming, that computes consistent bijective maps between all shape pairs in a given collection of initially unmatched shapes. As a fundamental distinction from previous work, our method aims to explicitly minimize the overall distortion, i.e., the average isometric distortion of the resulting maps over all shape pairs. We cast the problem as optimal path finding on a graph structure where vertices are maps between shape extremities. We exploit as much context information as possible using a dynamic programming based algorithm to approximate the optimal solution. Our method generates coarse multiple correspondences between shape extremities, as well as denser correspondences as by-product. We assess the performance on various mesh sequences of (nearly) isometric shapes. Our experiments show that, for isometric shape collections with non-uniform triangulation and noise, our method can compute relatively dense correspondences reasonably fast and outperform state of the art in terms of accuracy.Publication Open Access A diversity combination model incorporating an inward bias for interaural time-level difference cue integration in sound lateralization(Multidisciplinary Digital Publishing Institute (MDPI), 2020) N/A; Department of Computer Engineering; Department of Computer Engineering; Mojtahedi, Sina; Erzin, Engin; Ungan, Pekcan; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; College of Engineering; School of Medicine; N/A; 34503; N/AA sound source with non-zero azimuth leads to interaural time level differences (ITD and ILD). Studies on hearing system imply that these cues are encoded in different parts of the brain, but combined to produce a single lateralization percept as evidenced by experiments indicating trading between them. According to the duplex theory of sound lateralization, ITD and ILD play a more significant role in low-frequency and high-frequency stimulations, respectively. In this study, ITD and ILD, which were extracted from a generic head-related transfer functions, were imposed on a complex sound consisting of two low- and seven high-frequency tones. Two-alternative forced-choice behavioral tests were employed to assess the accuracy in identifying a change in lateralization. Based on a diversity combination model and using the error rate data obtained from the tests, the weights of the ITD and ILD cues in their integration were determined by incorporating a bias observed for inward shifts. The weights of the two cues were found to change with the azimuth of the sound source. While the ILD appears to be the optimal cue for the azimuths near the midline, the ITD and ILD weights turn to be balanced for the azimuths far from the midline.Publication Open Access Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2(American Society for Biochemistry and Molecular Biology (ASBMB), 2018) Jang, Hyunbum; Li, Zhigang; Sacks, David B.; Nussinov, Ruth; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Gürsoy, Attila; Keskin, Özlem; Özdemir, E. Sıla; Faculty Member; College of Engineering; Graduate School of Sciences and Engineering; 8745; 26605; N/AIQ motif-containing GTPase-activating proteins (IQGAPs) are scaffolding proteins playing central roles in cell-cell adhesion, polarity, and motility. The Rho GTPases Cdc42 and Rac1, in their GTP-bound active forms, interact with all three human IQGAPs. The IQGAP-Cdc42 interaction promotes metastasis by enhancing actin polymerization. However, despite their high sequence identity, Cdc42 and Rac1 differ in their interactions with IQGAP. Two Cdc42 molecules can bind to the Ex-domain and the RasGAP site of the GTPase-activating protein (GAP)related domain (GRD) of IQGAP and promote IQGAP dimerization. Only one Rac1 molecule might bind to the RasGAP site of GRD and may not facilitate the dimerization, and the exact mechanism of Cdc42 and Rac1 binding to IQGAP is unclear. Using all-atom molecular dynamics simulations, site-directed mutagenesis, and Western blotting, we unraveled the detailed mechanisms of Cdc42 and Rac1 interactions with IQGAP2. We observed that Cdc42 binding to the Ex-domain of GRD of IQGAP2 (GRD2) releases the Ex-domain at the C-terminal region of GRD2, facilitating IQGAP2 dimerization. Cdc42 binding to the Ex-domain promoted allosteric changes in the RasGAP site, providing a binding site for the second Cdc42 in the RasGAP site. Of note, the Cdc42 "insert loop" was important for the interaction of the first Cdc42 with the Ex-domain. By contrast, differences in Rac1 insert-loop sequence and structure precluded its interaction with the Ex-domain. Rac1 could bind only to the RasGAP site of apo-GRD2 and could not facilitate IQGAP2 dimerization. Our detailed mechanistic insights help decipher how Cdc42 can stimulate actin polymerization in metastasis.Publication Open Access Prediction of optimal folding routes of proteins that satisfy the principle of lowest entropy loss: dynamic contact maps and optimal control(Public Library of Science, 2010) Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Arkun, Yaman; Erman, Burak; Faculty Member; Faculty Member; College of Engineering; 108526; 179997An optimization model is introduced in which proteins try to evade high energy regions of the folding landscape, and prefer low entropy loss routes during folding. We make use of the framework of optimal control whose convenient solution provides practical and useful insight into the sequence of events during folding. We assume that the native state is available. As the protein folds, it makes different set of contacts at different folding steps. The dynamic contact map is constructed from these contacts. The topology of the dynamic contact map changes during the course of folding and this information is utilized in the dynamic optimization model. The solution is obtained using the optimal control theory. We show that the optimal solution can be cast into the form of a Gaussian Network that governs the optimal folding dynamics. Simulation results on three examples (CI2, Sso7d and Villin) show that folding starts by the formation of local clusters. Non-local clusters generally require the formation of several local clusters. Non-local clusters form cooperatively and not sequentially. We also observe that the optimal controller prefers "zipping" or small loop closure steps during folding. The folding routes predicted by the proposed method bear strong resemblance to the results in the literature.Publication Open Access The architecture of the TIR domain signalosome in the toll-like receptor-4 signaling pathway(Nature Publishing Group (NPG), 2015) VanWaes, Carter; Chen, Zhong; Tsai, Chung-Jung; Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Graduate School of Sciences and Engineering; College of Engineering; College of Sciences; N/A; 26605; 8745Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro-and anti-tumor responses. The organization of the assembly is critical to the understanding of how these key receptors control major signaling pathways in the cell. Although several models for individual interactions were proposed, the entire TIR-domain signalosome architecture has not been worked out, possibly due to its complexity. We employ a powerful algorithm, crystal structures and experimental data to model the TLR4 and its cluster. The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro-and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro-and anti-inflammatory pathways. The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD. Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points. The architectures are compatible with the currently-available experimental data and provide compelling insights into signaling in cancer and inflammation pathways.Publication Open Access Enriching traditional proteinprotein interaction networks with alternative conformations of proteins(Nature Publishing Group (NPG), 2017) Halakou, Farideh; Kılıç, Emel Şen; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Keskin, Özlem; Gürsoy, Attila; Faculty Member; College of Engineering; 26605; 8745Traditional Protein-Protein Interaction (PPI) networks, which use a node and edge representation, lack some valuable information about the mechanistic details of biological processes. Mapping protein structures to these PPI networks not only provides structural details of each interaction but also helps us to find the mutual exclusive interactions. Yet it is not a comprehensive representation as it neglects the conformational changes of proteins which may lead to different interactions, functions, and downstream signaling. In this study, we proposed a new representation for structural PPI networks inspecting the alternative conformations of proteins. We performed a large-scale study by creating breast cancer metastasis network and equipped it with different conformers of proteins. Our results showed that although 88% of proteins in our network has at least two structures in Protein Data Bank (PDB), only 22% of them have alternative conformations and the remaining proteins have different regions saved in PDB. However, using even this small set of alternative conformations we observed a considerable increase in our protein docking predictions. Our protein-protein interaction predictions increased from 54% to 76% using the alternative conformations. We also showed the benefits of investigating structural data and alternative conformations of proteins through three case studies.Publication Open Access Measuring construction for social, economic and environmental assessment(Emerald, 2019) İlhan, Bahriye; Department of Computer Engineering; Department of Computer Engineering; Yobas, Mümine Banu; Teaching Faculty; College of EngineeringPurpose: the purpose of this paper is to examine the issues that should be considered for a better gauge of the construction industry and built environment and to propose a set of indicators for measuring the social, economic and environmental value of construction. Design/methodology/approach: the indicators proposed in this study use Pearce's schema, which presents a framework to evaluate the socio-economic value of construction and its contribution to sustainable development. After analysing the problems faced by the industry, solutions are raised and finally indicators for each pillar of Pearce's schema are established through a literature review. Since the proposed indicators can be used for cross-country analysis, these comparisons are also presented as graphs including only those countries for which valid national data could be sourced from OECD databases. Findings: the issues, suggestions and indicators related to each concern about the main domains of the schema are addressed through the related literature and supported by available statistical data. Originality/value: although previous studies have drawn attention to measures for better evaluation of the construction industry and the built environment, this study, distinctively, presents an integrated approach in order to gauge the true value and impacts of construction in a more comprehensive way. The work's contribution to the body of knowledge is in revealing the hidden input and impact of construction on sustainable development by determining the barriers to this and their solutions, in addition to the proposal of relevant indicators.Publication Open Access Can a smartband be used for continuous implicit authentication in real life(Institute of Electrical and Electronics Engineers (IEEE), 2020) Ekiz, Deniz; Dardağan Yağmur Ceren; Ersoy, Cem; Department of Computer Engineering; Department of Computer Engineering; Can, Yekta Said; College of EngineeringThe use of cloud services that process privacy-sensitive information such as digital banking, pervasive healthcare, smart home applications requires an implicit continuous authentication solution, which will make these systems less vulnerable to the spoofing attacks. Physiological signals can be used for continuous authentication due to their uniqueness. Ubiquitous wrist-worn wearable devices are equipped with photoplethysmogram sensors, which enable us to extract heart rate variability (HRV) features. In this study, we show that these devices can be used for continuous physiological authentication for enhancing the security of the cloud, edge services, and IoT devices. A system that is suitable for the smartband framework comes with new challenges such as relatively low signal quality and artifacts due to placement, which were not encountered in full lead electrocardiogram systems. After the artifact removal, cleaned physiological signals are fed to the machine learning algorithms. In order to train our machine learning models, we collected physiological data using off-the-shelf smartbands and smartwatches in a real-life event. By applying a minimum quality threshold, we achieved a 3.96% Equal Error Rate. Performance evaluation shows that HRV is a strong candidate for continuous unobtrusive implicit physiological authentication.
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