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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; Mojtahedi, Sina; Erzin, Engin; Ungan, Pekcan; Faculty Member; Faculty Member; Department of Computer Engineering; 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 Metadata only A diversity combination model incorporating an inward bias for interaural time-level difference cue integration in sound lateralization(MDPI, 2020) N/A; N/A; Department of Computer Engineering; N/A; Mojtahedi, Sina; Erzin, Engin; Ungan, Pekcan; PhD Student; Faculty Member; Faculty Member; Department of Computer Engineering; 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 Metadata only A genome-wide functional screen identifies enhancer and protective genes for amyloid beta-peptide toxicity(Multidisciplinary Digital Publishing Institute (MDPI), 2023) Picon-Pages, Pol; Bosch-Morato, Monica; Subirana, Laia; Rubio-Moscardo, Francisca; Guivernau, Biuse; Fanlo-Ucar, Hugo; Herrera-Fernandez, Victor; Vicente, Ruben; Fernandez-Fernandez, Jose M.; Garcia-Ojalvo, Jordi; Oliva, Baldomero; Posas, Francesc; de Nadal, Eulalia; Munoz, Francisco J.; N/A; N/A; N/A; Department of Computer Engineering; Department of Computer Engineering; Zeylan, Melisa Ece; Şenyüz, Simge; Gürsoy, Attila; Keskin, Özlem; PhD Student; Master Student; Faculty Member; Faculty Member; Department of Computer Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; N/A; 8745; 26605Alzheimer's disease (AD) is known to be caused by amyloid beta-peptide (A beta) misfolded into beta-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in A beta toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing A beta(1-42). We identified 81 mammalian orthologue genes that enhance A beta(1-42) toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by A beta oligomers (oA beta). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that SURF4 silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, SURF4 silencing produced a significant reduction in cell death when cells were challenged with oA beta(1-42), whereas SURF4 overexpression induced A beta(1-42) cytotoxicity. In summary, we identified new enhancer and protective activities for A beta toxicity and showed that SURF4 contributes to oA beta(1-42) neurotoxicity by decreasing SOCE activity.Publication Metadata only A strategy based on protein-protein interface motifs may help in identifying drug off-targets(American Chemical Society (ACS), 2012) Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Computer Engineering; Keskin, Özlem; Gürsoy, Attila; Ergin, Billur Çelebi; Faculty Member; Faculty Member; Teaching Faculty; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; College of Engineering; 26605; 8745; 261792Networks are increasingly used to study the impact of drugs at the systems level. From the algorithmic standpoint, a drug can "attack" nodes or edges of a protein-protein interaction network In this work, we propose a new network strategy, "The Interface Attack", based on protein-protein interfaces. Similar interface architectures can occur between unrelated proteins. Consequently, in principle, a drug that binds to one has a certain probability of binding to others. The interface attack strategy simultaneously removes from the network all interactions that consist of similar interface motifs. This strategy is inspired by network pharmacology and allows inferring potential off-targets. We introduce a network model that we call "Protein Interface and Interaction Network (P2IN)", which is the integration of protein-protein interface structures and protein interaction networks. This interface based, network organization clarifies which protein pairs have structurally similar interfaces and which proteins may compete to bind the same surface region. We built the P2IN with the p53 signaling network and performed network robustness analysis. We show that (1) "hitting" frequent interfaces (a set of edges distributed around the network) might be as destructive as eleminating high degree proteins (hub nodes), (2) frequent interfaces are not always topologically critical elements in the network, and (3) interface attack may reveal functional changes in the system better than the attack of single proteins. In the off target detection case study, we found that drugs blocking the interface between CDK6 and CDKN2D may also affect the interaction between CDK4 and CDKN2D.Publication Metadata only Arl2-mediated allosteric release of farnesylated kras4b from shuttling factor pde delta(2018) Jang, Hyunbum; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Özdemir, E. Sıla; Gürsoy, Attila; Keskin, Özlem; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; College of Engineering; College of Engineering; N/A; 8745; 40548Proper localization of Ras proteins at the plasma membrane (PM) is crucial for their functions. To get to the PM, KRas4B and some other Ras family proteins bind to the PDE delta shuttling protein through their farnesylated hypervariable regions (HVRs). The docking of their famesyl (and to a lesser extent geranylgeranyl) in the hydrophobic pocket of PDE delta's stabilizes the interaction. At the PM, guanosine 5'-triphosphate (GTP)-bound Arf-like protein 2 (Arl2) assists in the release of Ras from the PDE delta. However, exactly how is still unclear. Using all-atom molecular dynamics simulations, we unraveled the detailed mechanism of Arl2-mediated release of KRas4B, the most abundant oncogenic Ras isoform, from PDE delta. We simulated ternary Arl2 PDE delta KRas4B HVR complexes and observed that Arl2 binding weakens the PDE delta farnesylated HVR interaction. Our detailed analysis showed that allosteric changes (involving beta 6 of PDE delta and additional PDE delta residues) compress the hydrophobic PDE delta pocket and push the HVR out. Mutating PDE delta residues that mediate allosteric changes in PDE delta terminates the release process. Mutant Ras proteins are enriched in human cancers, with currently no drugs in the clinics. This mechanistic account may inspire efforts to develop drugs suppressing oncogenic KRas4B release.Publication Open Access Mechanistic differences of activation of Rac1(P29S) and Rac1(A159V)(American Chemical Society (ACS), 2021) Jang, Hyunbum; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Şenyüz, Simge; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 26605; 8745Rac1 is a small GTPase that plays key roles in actin reorganization, cell motility, and cell survival/growth as well as in various cancer types and neurodegenerative diseases. Similar to other Ras superfamily GTPases, Rac1 switches between active GTP-bound and inactive GDP-bound states. Switch I and II regions open and close during GDP/GTP exchange. P29S and A159V (paralogous to K-Ras(A146)) mutations are the two most common somatic mutations of Rac1. Rac1(P2)(9S)( )is a known hotspot for melanoma, whereas Rac1(A159V) most commonly occurs in head and neck cancer. To investigate how these substitutions induce the Rac1 dynamics, we used atomistic molecular dynamics simulations on the wild-type Rac1 and two mutant systems (P29S and A159V) in the GTP bound state, and on the wild-type Rac1 and P29S mutated system in the GDP bound state. Here, we show that P29S and A159V mutations activate Rac1 with different mechanisms. In Rac1(P29S)-GTP, the substitution increases the flexibility of Switch I based on RMSF and dihedral angle calculations and leads to an open conformation. We propose that the open Switch I conformation is one of the underlying reasons for rapid GDP/GTP exchange of Rac1(P29S). On the other hand, in Rac1(A159V)-GTP, some of the contacts of the guanosine ring of GTP with Rac1 are temporarily lost, enabling the guanosine ring to move toward Switch I and subsequently close the switch. Rac1(A159V)-GTP adopts a Ras state 2 like conformation, where both switch regions are in closed conformation and Thr35 forms a hydrogen bond with the nucleotide.Publication Open Access Molecular simulations of MOF membranes for separation of ethane/ethene and ethane/methane mixtures(Royal Society of Chemistry (RSC), 2017) Altıntaş, Çiğdem; Department of Chemical and Biological Engineering; Department of Computer Engineering; Keskin, Seda; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; College of Engineering; 40548Metal organic framework (MOF) membranes have been widely investigated for gas separation applications. Several MOFs have been recently examined for selective separation of C2H6. Considering the large number of available MOFs, it is not possible to fabricate and test the C2H6 separation performance of every single MOF membrane using purely experimental methods. In this study, we used molecular simulations to assess the membrane-based C2H6/C2H4 and C2H6/CH4 separation performances of 175 different MOF structures. This is the largest number of MOF membranes studied to date for C2H6 separation. We computed adsorption selectivity, diffusion selectivity, membrane selectivity and gas permeability of MOFs for C2H6/C2H4 and C2H6/CH4 mixtures. Our results show that a significant number of MOF membranes are C2H6 selective for C2H6/C2H4 separation in contrast to traditional nanoporous materials. Selectivity and permeability of MOF membranes were compared with other membrane materials, such as polymers, zeolites, and carbon molecular sieves. Several MOFs were identified to exceed the upper bound established for polymeric membranes and many MOF membranes exhibited higher gas permeabilities than zeolites and carbon molecular sieves. Examining the structure–performance relations of MOF membranes revealed that MOFs with cavity diameters between 6 and 9 A, porosities lower than 0.50, and surface areas between 500–1000 m2 g 1 have high C2H6 selectivities. The results of this study will be useful to guide the experiments to the most promising MOF membranes for efficient separation of C2H6 and to accelerate the development of new MOFs with high C2H6 selectivities.Publication Open Access Normal mode analysis of KRas4B reveals partner specific dynamics(American Chemical Society (ACS), 2021) Jang, Hyunbum; Nussinov, Ruth; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Computer Engineering; Tunçbağ, Nurcan; Gürsoy, Attila; Keskin, Özlem; Eren, Meryem; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Department of Computer Engineering; School of Medicine; College of Engineering; Graduate School of Sciences and Engineering; 245513; 8745; 26605; N/ARas GTPase interacts with its regulators and downstream effectors for its critical function in cellular signaling. Targeting the disrupted mechanisms in Ras-related human cancers requires understanding the distinct dynamics of these protein-protein interactions. We performed normal mode analysis (NMA) of KRas4B in wild-type or mutant monomeric and neurofibromin-1 (NF1), Son of Sevenless 1 (SOS1) or Raf-1 bound dimeric conformational states to reveal partner-specific dynamics of the protein. Gaussian network model (GNM) analysis showed that the known KRas4B lobes further partition into subdomains upon binding to its partners. Furthermore, KRas4B interactions with different partners suppress the flexibility in not only their binding sites but also distant residues in the allosteric lobe in a partner-specific way. The conformational changes can be driven by intrinsic residue fluctuations of the open state KRas4B-GDP, as we illustrated with anisotropic network model (ANM) analysis. The allosteric paths connecting the nucleotide binding residues to the allosteric site at alpha 3-L7 portray differences in the inactive and active states. These findings help in understanding the partner-specific KRas4B dynamics, which could be utilized for therapeutic targeting.Publication Metadata only PDEδ binding to ras isoforms provides a route to proper membrane localization(Amer Chemical Soc, 2017) Jang, Hyunbum; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Muratçıoğlu, Serena; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745To signal, Ras isoforms must be enriched at the plasma membrane (PM). It was suggested that phosphodies-terase-delta (PDE delta) can bind and shuttle some farnesylated Ras isoforms to the PM, but not all. Among these, interest focused on K-Ras4B, the most abundant oncogenic Ras isoform. To study PDE delta/Ras interactions, we modeled and simulated the PDE delta/K-Ras4B complex. We obtained structures, which were similar to two subsequently determined crystal structures. We next modeled and simulated complexes of PDE delta with the farnesylated hypervariable regions K-Ras4A and N-Ras. Earlier data suggested that PDE delta extracts K-Ras4B and N-Ras from the PM, but surprisingly not K-kas4A. Earlier analysis of the crystal structures advanced that the presence of large/charged residues adjacent to the farnesylated site precludes the PDE delta interaction. Here, we show that PDE delta can bind to farnesylated K-Ras4A and N-Ras like K-Ras4B, albeit not as strongly. This weaker binding, coupled with the stronger anchoring of K-Ras4A in the membrane (but not of electrostatically neutral N-Ras), can explain the observation why PDE delta is unable to effectively extract K-Ras4A. We thus propose that farnesylated Ras isoforms can bind PDE delta to fulfill the required PM enrichment, and argue that the different environments, PM versus solution, can resolve apparently puzzling Ras observations. These are novel insights that would not be expected based on the crystal structures alone, which provide an elegant rationale for previously puzzling observations of the differential effects of PDE delta on farnesylated Ras family proteins.Publication Metadata only Predicting protein-protein interactions from the molecular to the proteome level(Amer Chemical Soc, 2016) Tunçbağ, Nurcan; Department of Chemical and Biological Engineering; Department of Computer Engineering; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; College of Engineering; 26605; 8745Identification of protein protein interactions (PPIs) is at the center of molecular biology considering the unquestionable role of proteins in cells. Combinatorial interactions result in a repertoire of multiple functions; hence, knowledge of PPI and binding regions naturally serve to functional proteomics and drug discovery. Given experimental limitations to find all interactions in a proteome, computational prediction/modeling of protein interactions is a prerequisite to proceed on the way to complete interactions at the proteome level. This review aims to provide a background on PPIs and their types. Computational methods for PPI predictions can use a variety of biological data including sequence-, evolution-, expression-, and structure-based data. Physical and statistical modeling are commonly used to integrate these data and infer PPI predictions. We review and list the state-of-the-art methods, servers, databases, and tools for protein-protein interaction prediction.