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Author Euro, L.; Konovalova, S.; Asin-Cayuela, J.; Tulinius, M.; Griffin, H.; Horvath, R.; Taylor, R.W.; Chinnery, P.F.; Schara, U.; Thorburn, D.R.; Suomalainen, A.; Chihade, J.; Tyynismaa, H. openurl 
  Title Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation Type Journal Article
  Year 2015 Publication Abbreviated Journal Frontiers in Genetics  
  Volume 6 Issue Pages 21  
  Keywords  
  Abstract The accuracy of mitochondrial protein synthesis is dependent on the coordinated action of nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtARSs) and the mitochondrial DNA-encoded tRNAs. The recent advances in whole-exome sequencing have revealed the importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS (out of 19) is now recognized as a disease gene for mitochondrial disease. Typically, defects in each mtARS have been identified in one tissue-specific disease, most commonly affecting the brain, or in one syndrome. However, mutations in the AARS2 gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS) have been reported both in patients with infantile-onset cardiomyopathy and in patients with childhood to adulthood-onset leukoencephalopathy. We present here an investigation of the effects of the described mutations on the structure of the synthetase, in an effort to understand the tissue-specific outcomes of the different mutations. The mtAlaRS differs from the other mtARSs because in addition to the aminoacylation domain, it has a conserved editing domain for deacylating tRNAs that have been mischarged with incorrect amino acids. We show that the cardiomyopathy phenotype results from a single allele, causing an amino acid change R592W in the editing domain of AARS2, whereas the leukodystrophy mutations are located in other domains of the synthetase. Nevertheless, our structural analysis predicts that all mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation. According to our model, the cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients. These predictions provide a hypothesis for the molecular basis of the distinct tissue-specific phenotypic outcomes.  
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  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47113  
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Author Hirakis, S.; Boras, B.; Votapka, L.; Malmstrom, R.; McCulloch, A.; Amaro, R. url  openurl
  Title Bridging scales through multiscale modeling: a case study on protein kinase A Type Journal Article
  Year 2015 Publication Abbreviated Journal Frontiers in Physiology  
  Volume 6 Issue Pages 250  
  Keywords milestoning,structural biology,flexibility project  
  Abstract The goal of multiscale modeling in biology is to use structurally based physico-chemical models to integrate across temporal and spatial scales of biology and thereby improve mechanistic understanding of, for example, how a single mutation can alter organism-scale phenotypes. This approach may also inform therapeutic strategies or identify candidate drug targets that might otherwise have been overlooked. However, in many cases, it remains unclear how best to synthesize information obtained from various scales and analysis approaches, such as atomistic molecular models, Markov state models (MSM), subcellular network models, and whole cell models. In this paper, we use protein kinase A (PKA) activation as a case study to explore how computational methods that model different physical scales can complement each other and integrate into an improved multiscale representation of the biological mechanisms. Using measured crystal structures, we show how molecular dynamics (MD) simulations coupled with atomic-scale MSMs can provide conformations for Brownian dynamics (BD) simulations to feed transitional states and kinetic parameters into protein-scale MSMs. We discuss how milestoning can give reaction probabilities and forward-rate constants of cAMP association events by seamlessly integrating MD and BD simulation scales. These rate constants coupled with MSMs provide a robust representation of the free energy landscape, enabling access to kinetic and thermodynamic parameters unavailable from current experimental data. These approaches have helped to illuminate the cooperative nature of PKA activation in response to distinct cAMP binding events. Collectively, this approach exemplifies a general strategy for multiscale model development that is applicable to a wide range of biological problems.  
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  Series Volume Series Issue Edition  
  ISSN 1664-042x ISBN Medium  
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  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47130  
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Author Brender, J.R.; Zhang, Y. url  openurl
  Title Predicting the Effect of Mutations on Protein-Protein Binding Interactions through Structure-Based Interface Profiles Type Journal Article
  Year 2015 Publication Abbreviated Journal PLoS Computational Biology  
  Volume 11 Issue 26506533 Pages e1004494--e1004494  
  Keywords structural biology,ppi,modelling,in silico tool  
  Abstract The formation of protein-protein complexes is essential for proteins to perform their physiological functions in the cell. Mutations that prevent the proper formation of the correct complexes can have serious consequences for the associated cellular processes. Since experimental determination of protein-protein binding affinity remains difficult when performed on a large scale, computational methods for predicting the consequences of mutations on binding affinity are highly desirable. We show that a scoring function based on interface structure profiles collected from analogous protein-protein interactions in the PDB is a powerful predictor of protein binding affinity changes upon mutation. As a standalone feature, the differences between the interface profile score of the mutant and wild-type proteins has an accuracy equivalent to the best all-atom potentials, despite being two orders of magnitude faster once the profile has been constructed. Due to its unique sensitivity in collecting the evolutionary profiles of analogous binding interactions and the high speed of calculation, the interface profile score has additional advantages as a complementary feature to combine with physics-based potentials for improving the accuracy of composite scoring approaches. By incorporating the sequence-derived and residue-level coarse-grained potentials with the interface structure profile score, a composite model was constructed through the random forest training, which generates a Pearson correlation coefficient >0.8 between the predicted and observed binding free-energy changes upon mutation. This accuracy is comparable to, or outperforms in most cases, the current best methods, but does not require high-resolution full-atomic models of the mutant structures. The binding interface profiling approach should find useful application in human-disease mutation recognition and protein interface design studies.  
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  Series Volume Series Issue Edition  
  ISSN 1553-734x ISBN Medium  
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  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47142  
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Author Lee, C.‐U.; Hahne, G.; Hanske, J.; Bange, T.; Bier, D.; Rademacher, C.; Hennig, S.; Grossmann, T.N. openurl 
  Title Redox Modulation of PTEN Phosphatase Activity by Hydrogen Peroxide and Bisperoxidovanadium Complexes Type Journal Article
  Year 2015 Publication Abbreviated Journal Angewandte Chemie International Edition  
  Volume 54 Issue 46 Pages 13796-13800  
  Keywords pdb,gene:PTEN,pdb:5BUG,pdb:5BZX,pdb:5BZZ  
  Abstract PTEN is a dual-specificity protein tyrosine phosphatase. As one of the central tumor suppressors, a thorough regulation of its activity is essential for proper cellular homeostasis. The precise implications of PTEN inhibition by reactive oxygen species (e.g. H2O2) and the subsequent structural consequences remain elusive. To study the effects of PTEN inhibition, bisperoxidovanadium (bpV) complexes serve as important tools with the potential for the treatment of nerve injury or cardiac ischemia. However, their mode of action is unknown, hampering further optimization and preventing therapeutic applications. Based on protein crystallography, mass spectrometry, and NMR spectroscopy, we elucidate the molecular basis of PTEN inhibition by H2O2 and bpV complexes. We show that both molecules inhibit PTEN via oxidative mechanisms resulting in the formation of the same intramolecular disulfide, therefore enabling the reactivation of PTEN under reductive conditions.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1521-3773 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47153  
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Author Plattner, N.; Noé, F. url  openurl
  Title Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models Type Journal Article
  Year 2015 Publication Abbreviated Journal Nature Communications  
  Volume 6 Issue Pages 7653  
  Keywords milestoning,structural biology,flexibility project  
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  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47157  
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Author Shukla, D.; Hernández, C.X.; Weber, J.K.; Pande, V.S. url  openurl
  Title Markov State Models Provide Insights into Dynamic Modulation of Protein Function Type Journal Article
  Year 2015 Publication Abbreviated Journal Accounts of Chemical Research  
  Volume 48 Issue 2 Pages 414--422  
  Keywords milestoning,structural biology,flexibility project  
  Abstract Protein function is inextricably linked to protein dynamics. As we move from a static structural picture to a dynamic ensemble view of protein structure and function, novel computational paradigms are required for observing and understanding conformational dynamics of proteins and its functional implications. In principle, molecular dynamics simulations can provide the time evolution of atomistic models of proteins, but the long time scales associated with functional dynamics make it difficult to observe rare dynamical transitions. The issue of extracting essential functional components of protein dynamics from noisy simulation data presents another set of challenges in obtaining an unbiased understanding of protein motions. Therefore, a methodology that provides a statistical framework for efficient sampling and a human-readable view of the key aspects of functional dynamics from data analysis is required. The Markov state model (MSM), which has recently become popular worldwide for studying protein dynamics, is an example of such a framework. In this Account, we review the use of Markov state models for efficient sampling of the hierarchy of time scales associated with protein dynamics, automatic identification of key conformational states, and the degrees of freedom associated with slow dynamical processes. Applications of MSMs for studying long time scale phenomena such as activation mechanisms of cellular signaling proteins has yielded novel insights into protein function. In particular, from MSMs built using large-scale simulations of GPCRs and kinases, we have shown that complex conformational changes in proteins can be described in terms of structural changes in key structural motifs or “molecular switches” within the protein, the transitions between functionally active and inactive states of proteins proceed via multiple pathways, and ligand or substrate binding modulates the flux through these pathways. Finally, MSMs also provide a theoretical toolbox for studying the effect of nonequilibrium perturbations on conformational dynamics. Considering that protein dynamics in vivo occur under nonequilibrium conditions, MSMs coupled with nonequilibrium statistical mechanics provide a way to connect cellular components to their functional environments. Nonequilibrium perturbations of protein folding MSMs reveal the presence of dynamically frozen glass-like states in their conformational landscape. These frozen states are also observed to be rich in β-sheets, which indicates their possible role in the nucleation of β-sheet rich aggregates such as those observed in amyloid-fibril formation. Finally, we describe how MSMs have been used to understand the dynamical behavior of intrinsically disordered proteins such as amyloid-β, human islet amyloid polypeptide, and p53. While certainly not a panacea for studying functional dynamics, MSMs provide a rigorous theoretical foundation for understanding complex entropically dominated processes and a convenient lens for viewing protein motions.  
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  Series Volume Series Issue Edition  
  ISSN 0001-4842 ISBN Medium  
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  Notes Approved no  
  Call Number (up) AG @ matthewjvarga @ Serial 47165  
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Author Sargent, B.A.; Srinivasan, S.; Speck, A.; Volk, K.; Kemper, C.; Reach, W.T.; Lagadec, E.; Bernard, J.-P.; McDonald, I.; Meixner, M. openurl 
  Title Spitzer-IRS Spectroscopic Studies of Oxygen-Rich Asymptotic Giant Branch Star and Red Supergiant Star Dust Properties Type Conference Article
  Year 2015 Publication Abbreviated Journal  
  Volume Issue Pages 216.03-216.03  
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  Series Editor Series Title Abbreviated Series Title American Astronomical Society Meeting Abstracts  
  Series Volume 225 Series Issue Edition  
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  Notes proceedings Approved no  
  Call Number (up) ASIAA @ ciska @ Serial 41812  
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Author Sloan, G.C.; Groenewegen, M.; Srinivasan, S.; Lagadec, E.; Kraemer, K.E.; McDonald, I.; Boyer, M.L.; Zijlstra, A.; Kemper, C. openurl 
  Title Dust and metallicity in carbon stars Type Conference Article
  Year 2015 Publication Abbreviated Journal  
  Volume Issue Pages 216.04-216.04  
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  Language Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title American Astronomical Society Meeting Abstracts  
  Series Volume 225 Series Issue Edition  
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  Notes proceedings Approved no  
  Call Number (up) ASIAA @ ciska @ Serial 41813  
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Author Naslim, N.; Kemper, F.; Madden, S.C.; Hony, S.; Chu, Y.-H.; Galliano, F.; Bot, C.; Yang, Y.; Seok, J.; Oliveira, J.M.; van Loon, J.T.; Meixner, M.; Li, A.; Hughes, A.; Gordon, K.D.; Otsuka, M.; Hirashita, H.; Morata, O.; Lebouteiller, V.; Indebetouw, R.; Srinivasan, S.; Bernard, J.-P.; Reach, W.T. doi  openurl
  Title Molecular hydrogen emission in the interstellar medium of the Large Magellanic Cloud Type Journal Article
  Year 2015 Publication Mon.~Not.~R.~Astron.~Soc. Abbreviated Journal  
  Volume 446 Issue 3 Pages 2490-2504  
  Keywords ISM: molecules; photodissociation region (PDR); galaxies: ISM; Magellanic Cloud; infrared: ISM  
  Abstract We present the detection and analysis of molecular hydrogen emission towards ten interstellar regions in the Large Magellanic Cloud. We examined low-resolution infrared spectral maps of 12 regions obtained with the Spitzer infrared spectrograph (IRS). The pure rotational 0-0 transitions of H2 at 28.2 and 17.1 μm are detected in the IRS spectra for 10 regions. The higher level transitions are mostly upper limit measurements except for three regions, where a 3σ detection threshold is achieved for lines at 12.2 and 8.6 μm. The excitation diagrams of the detected H2 transitions are used to determine the warm H2 gas column density and temperature. The single-temperature fits through the lower transition lines give temperatures in the range 86-137 K. The bulk of the excited H2 gas is found at these temperatures and contributes ˜5-17 per cent to the total gas mass. We find a tight correlation of the H2 surface brightness with polycyclic aromatic hydrocarbon and total infrared emission, which is a clear indication of photoelectric heating in photodissociation regions. We find the excitation of H2 by this process is equally efficient in both atomic- and molecular-dominated regions. We also present the correlation of the warm H2 physical conditions with dust properties. The warm H2 mass fraction and excitation temperature show positive correlations with the average starlight intensity, again supporting H2 excitation in photodissociation regions.  
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  Notes refereed; Owner: ciska; Added to JabRef: 2015.04.15 Approved no  
  Call Number (up) ASIAA @ ciska @ Serial 41815  
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Author Ruffle, P.M.E.; Kemper, F.; Jones, O.C.; Sloan, G.C.; Kraemer, K.E.; Woods, P.M.; Boyer, M.L.; Srinivasan, S.; Antoniou, V.; Lagadec, E.; Matsuura, M.; McDonald, I.; Oliveira, J.M.; Sargent, B.A.; Sewiło, M.; Szczerba, R.; van Loon, J.T.; Volk, K.; Zijlstra, A.A. openurl 
  Title Spitzer infrared Spectrograph point source classification in the Small Magellanic Cloud Type Journal Article
  Year 2015 Publication Mon.~Not.~R.~Astron.~Soc. Abbreviated Journal  
  Volume Issue Pages  
  Keywords my_papers  
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  Notes submitted; Owner: ciska; Added to JabRef: 2015.03.04 Approved no  
  Call Number (up) ASIAA @ ciska @ Serial 41816  
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