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Author Yogurtcu, O.N.; Johnson, M.E. url  openurl
  Title Theory of bi-molecular association dynamics in 2D for accurate model and experimental parameterization of binding rates Type Journal Article
  Year 2015 Publication Abbreviated Journal J Chem Phys  
  Volume 143 Issue 8 Pages 084117  
  Keywords Jhu, Fpr, Cme  
  Abstract The dynamics of association between diffusing and reacting molecular species are routinely quantified using simple rate-equation kinetics that assume both well-mixed concentrations of species and a single rate constant for parameterizing the binding rate. In two-dimensions (2D), however, even when systems are well-mixed, the assumption of a single characteristic rate constant for describing association is not generally accurate, due to the properties of diffusional searching in dimensions d ≤ 2. Establishing rigorous bounds for discriminating between 2D reactive systems that will be accurately described by rate equations with a single rate constant, and those that will not, is critical for both modeling and experimentally parameterizing binding reactions restricted to surfaces such as cellular membranes. We show here that in regimes of intrinsic reaction rate (ka) and diffusion (D) parameters ka/D > 0.05, a single rate constant cannot be fit to the dynamics of concentrations of associating species independently of the initial conditions. Instead, a more sophisticated multi-parametric description than rate-equations is necessary to robustly characterize bimolecular reactions from experiment. Our quantitative bounds derive from our new analysis of 2D rate-behavior predicted from Smoluchowski theory. Using a recently developed single particle reaction-diffusion algorithm we extend here to 2D, we are able to test and validate the predictions of Smoluchowski theory and several other theories of reversible reaction dynamics in 2D for the first time. Finally, our results also mean that simulations of reactive systems in 2D using rate equations must be undertaken with caution when reactions have ka/D > 0.05, regardless of the simulation volume. We introduce here a simple formula for an adaptive concentration dependent rate constant for these chemical kinetics simulations which improves on existing formulas to better capture non-equilibrium reaction dynamics from dilute to dense systems.  
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  Corporate Author Thesis  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0021-9606 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46618  
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Author Pan, X.; Schwartz, S.D. url  openurl
  Title Free energy surface of the Michaelis complex of lactate dehydrogenase: a network analysis of microsecond simulations Type Journal Article
  Year 2015 Publication Abbreviated Journal J Phys Chem B  
  Volume 119 Issue 17 Pages 5430-5436  
  Keywords  
  Abstract It has long been recognized that the structure of a protein creates a hierarchy of conformations interconverting on multiple time scales. The conformational heterogeneity of the Michaelis complex is of particular interest in the context of enzymatic catalysis in which the reactant is usually represented by a single conformation of the enzyme/substrate complex. Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of two forms of the cofactor nicotinamide adenine dinucleotide (NADH and NAD(+)). Recent experimental results suggest that multiple substates exist within the Michaelis complex of LDH, and they show a strong variance in their propensity toward the on-enzyme chemical step. In this study, microsecond-scale all-atom molecular dynamics simulations were performed on LDH to explore the free energy landscape of the Michaelis complex, and network analysis was used to characterize the distribution of the conformations. Our results provide a detailed view of the kinetic network of the Michaelis complex and the structures of the substates at atomistic scales. They also shed light on the complete picture of the catalytic mechanism of LDH.  
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  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1520-6106 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46553  
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Author Masterson, J.E.; Schwartz, S.D. doi  openurl
  Title Evolution Alters the Enzymatic Reaction Coordinate of Dihydrofolate Reductase Type Journal Article
  Year 2015 Publication Abbreviated Journal The Journal of Physical Chemistry B  
  Volume 119 Issue 3 Pages 989-996  
  Keywords  
  Abstract How evolution has affected enzyme function is a topic of great interest in the field of biophysical chemistry. Evolutionary changes from Escherichia coli dihydrofolate reductase (ecDHFR) to human dihydrofolate reductase (hsDHFR) have resulted in increased catalytic efficiency and an altered dynamic landscape in the human enzyme. Here, we show that a subpicosecond protein motion is dynamically coupled to hydride transfer catalyzed by hsDHFR but not ecDHFR. This motion propagates through residues that correspond to mutational events along the evolutionary path from ecDHFR to hsDHFR. We observe an increase in the variability of the transition states, reactive conformations, and times of barrier crossing in the human system. In the hsDHFR active site, we detect structural changes that have enabled the coupling of fast protein dynamics to the reaction coordinate. These results indicate a shift in the DHFR family to a form of catalysis that incorporates rapid protein dynamics and a concomitant shift to a more flexible path through reactive phase space.  
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  Corporate Author Thesis  
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  Language Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1520-6106 ISBN Medium  
  Area Expedition Conference  
  Notes NULL Times cited: 12 Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46517  
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Author Hein, M. Y.; Hubner, N. C.; Poser, I.; Cox, J.; Nagaraj, N.; Toyoda, Y.; Gak, I. A.; Weisswange, I.; Mansfeld, J.; Buchholz, F.; Hyman, A. A.; Mann, M. doi  openurl
  Title A Human Interactome in Three Quantitative Dimensions Organized by Stoichiometries and Abundances Type Journal Article
  Year 2015 Publication Abbreviated Journal Cell  
  Volume 163 Issue 3 Pages 712-723  
  Keywords  
  Abstract Summary The organization of a cell emerges from the interactions in protein networks. The interactome is critically dependent on the strengths of interactions and the cellular abundances of the connected proteins, both of which span orders of magnitude. However, these aspects have not yet been analyzed globally. Here, we have generated a library of HeLa cell lines expressing 1,125 GFP-tagged proteins under near-endogenous control, which we used as input for a next-generation interaction survey. Using quantitative proteomics, we detect specific interactions, estimate interaction stoichiometries, and measure cellular abundances of interacting proteins. These three quantitative dimensions reveal that the protein network is dominated by weak, substoichiometric interactions that play a pivotal role in defining network topology. The minority of stable complexes can be identified by their unique stoichiometry signature. This study provides a rich interaction dataset connecting thousands of proteins and introduces a framework for quantitative network analysis.  
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  Language Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1097-4172 (Electronic)\textbackslash\r0092-8674 (Linking) ISBN Medium  
  Area Expedition Conference  
  Notes Times cited: 690 Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46438  
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Author Wan, C.; Borgeson, B.; Phanse, S.; Tu, F.; Drew, K.; Clark, G.; Xiong, X.; Kagan, O.; Kwan, J.; Bezginov, A.; Chessman, K.; Pal, S.; Cromar, G.; Papoulas, O.; Ni, Z.; Boutz, D.R.; Stoilova, S.; Havugimana, P.C.; Guo, X.; Malty, R.H.; Sarov, M.; Greenblatt, J.; Babu, M.; Derry, W.B.; R. Tillier, E.; Wallingford, J.B.; Parkinson, J.; Marcotte, E.M.; Emili, A. doi  openurl
  Title Panorama of ancient metazoan macromolecular complexes Type Journal Article
  Year 2015 Publication Abbreviated Journal Nature  
  Volume 525 Issue 7569 Pages 339-344  
  Keywords Animals Biochemical Datasets as Topic Evolution Fractionation Humans Metazoa Molecular Multiprotein Complexes Multiprotein Complexes: chemistry Multiprotein Complexes: metabolism Protein Interaction Mapping Protein Interaction Maps Protein complexes Proteomics Reproducibility of Results Systems Biology Tandem Mass Spectrometry  
  Abstract Macromolecular complexes are essential to conserved biological processes, but their prevalence across animals is unclear. By combining extensive biochemical fractionation with quantitative mass spectrometry, here we directly examined the composition of soluble multiprotein complexes among diverse metazoan models. Using an integrative approach, we generated a draft conservation map consisting of more than one million putative high-confidence co-complex interactions for species with fully sequenced genomes that encompasses functional modules present broadly across all extant animals. Clustering reveals a spectrum of conservation, ranging from ancient eukaryotic assemblies that have probably served cellular housekeeping roles for at least one billion years, ancestral complexes that have accrued contemporary components, and rarer metazoan innovations linked to multicellularity. We validated these projections by independent co-fractionation experiments in evolutionarily distant species, affinity purification and functional analyses. The comprehensiveness, centrality and modularity of these reconstructed interactomes reflect their fundamental mechanistic importance and adaptive value to animal cell systems.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0028-0836 ISBN Medium  
  Area Expedition Conference  
  Notes Times cited: 288 Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46421  
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Author Dzierlenga, M.W.; Antoniou, D.; Schwartz, S.D. doi  openurl
  Title Another Look at the Mechanisms of Hydride Transfer Enzymes with Quantum and Classical Transition Path Sampling Type Journal Article
  Year 2015 Publication Abbreviated Journal The Journal of Physical Chemistry Letters  
  Volume 6 Issue 7 Pages 1177-1181  
  Keywords  
  Abstract The mechanisms involved in enzymatic hydride transfer have been studied for years, but questions remain due, in part, to the difficulty of probing the effects of protein motion and hydrogen tunneling. In this study, we use transition path sampling (TPS) with normal mode centroid molecular dynamics (CMD) to calculate the barrier to hydride transfer in yeast alcohol dehydrogenase (YADH) and human heart lactate dehydrogenase (LDH). Calculation of the work applied to the hydride allowed for observation of the change in barrier height upon inclusion of quantum dynamics. Similar calculations were performed using deuterium as the transferring particle in order to approximate kinetic isotope effects (KIEs). The change in barrier height in YADH is indicative of a zero-point energy (ZPE) contribution and is evidence that catalysis occurs via a protein compression that mediates a near-barrierless hydride transfer. Calculation of the KIE using the difference in barrier height between the hydride and deuteride agreed well with experimental results.  
  Address  
  Corporate Author Thesis  
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  Language Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1948-7185 ISBN Medium  
  Area Expedition Conference  
  Notes NULL Times cited: 21 Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46386  
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Author Cook, W.J.; Senkovich, O.; Hernandez, A.; Speed, H.; Chattopadhyay, D. doi  openurl
  Title Biochemical and structural characterization of Cryptosporidium parvum Lactate dehydrogenase Type Journal Article
  Year 2015 Publication Abbreviated Journal International Journal of Biological Macromolecules  
  Volume 74 Issue Pages 608-619  
  Keywords Amino Acid Sequence Binding Sites Cryptosporidium parvum Cryptosporidium parvum: enzymology Enzyme Activation Kinetics L-Lactate Dehydrogenase L-Lactate Dehydrogenase: chemistry L-Lactate Dehydrogenase: metabolism Models Molecular Molecular Sequence Data NAD NAD: chemistry NAD: metabolism NADP NADP: chemistry NADP: metabolism Protein Binding Protein Conformation Sequence Alignment Substrate Specificity  
  Abstract The protozoan parasite Cryptosporidium parvum causes waterborne diseases worldwide. There is no effective therapy for C. parvum infection. The parasite depends mainly on glycolysis for energy production. Lactate dehydrogenase is a major regulator of glycolysis. This paper describes the biochemical characterization of C. parvum lactate dehydrogenase and high resolution crystal structures of the apo-enzyme and four ternary complexes. The ternary complexes capture the enzyme bound to NAD/NADH or its 3-acetylpyridine analog in the cofactor binding pocket, while the substrate binding site is occupied by one of the following ligands: lactate, pyruvate or oxamate. The results reveal distinctive features of the parasitic enzyme. For example, C. parvum lactate dehydrogenase prefers the acetylpyridine analog of NADH as a cofactor. Moreover, it is slightly less sensitive to gossypol inhibition compared with mammalian lactate dehydrogenases and not inhibited by excess pyruvate. The active site loop and the antigenic loop in C. parvum lactate dehydrogenase are considerably different from those in the human counterpart. Structural features and enzymatic properties of C. parvum lactate dehydrogenase are similar to enzymes from related parasites. Structural comparison with malate dehydrogenase supports a common ancestry for the two genes.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0141-8130 ISBN Medium  
  Area Expedition Conference  
  Notes NULL Times cited: 12 Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46374  
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Author Tuñón, I.; Laage, D.; Hynes, J.T. url  openurl
  Title Are there dynamical effects in enzyme catalysis? Some thoughts concerning the enzymatic chemical step Type Journal Article
  Year 2015 Publication Abbreviated Journal Arch Biochem Biophys  
  Volume 582 Issue Pages 42-55  
  Keywords Dynamical effects Enzyme catalysis Transition State Theory  
  Abstract We offer some thoughts on the much debated issue of dynamical effects in enzyme catalysis, and more specifically on their potential role in the acceleration of the chemical step. Since the term ‘dynamics’ has been used with different meanings, we find it useful to first return to the Transition State Theory rate constant, its assumptions and the choices it involves, and detail the various sources of deviations from it due to dynamics (or not). We suggest that much can be learned about the key current questions for enzyme catalysis from prior extensive studies of dynamical and other effects in the case of reactions in solution. We analyze dynamical effects both in the neighborhood of the transition state and far from it, together with the situation when quantum nuclear motion is central to the reaction, and we illustrate our discussion with various examples of enzymatic reactions.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1096-0384 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46369  
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Author Truhlar, D.G. url  openurl
  Title Transition state theory for enzyme kinetics Type Journal Article
  Year 2015 Publication Abbreviated Journal Arch Biochem Biophys  
  Volume 582 Issue Pages 10-17  
  Keywords Enzyme kinetics Free energy Quantum effects Transition state theory Tunneling  
  Abstract This article is an essay that discusses the concepts underlying the application of modern transition state theory to reactions in enzymes. Issues covered include the potential of mean force, the quantization of vibrations, the free energy of activation, and transmission coefficients to account for nonequilibrium effect, recrossing, and tunneling.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0003-9861 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46364  
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Author Bhowmick, A.; Head-Gordon, T. doi  openurl
  Title A Monte Carlo Method for Generating Side Chain Structural Ensembles Type Journal Article
  Year 2015 Publication Abbreviated Journal Structure  
  Volume 23 Issue 1 Pages 44-55  
  Keywords  
  Abstract We report a Monte Carlo side chain entropy (MC-SCE) method that uses a physical energy function inclusive of long-range electrostatics and hydrophobic potential of mean force, coupled with both backbone variations and a backbone dependent side chain rotamer library, to describe protein conformational ensembles. Using the MC-SCE method in conjunction with backbone variability, we can reliably determine the side chain rotamer populations derived from both room temperature and cryogenically cooled X-ray crystallographic structures for CypA and H-Ras and NMR J-coupling constants for CypA, Eglin-C, and the DHFR product binary complexes E:THF and E:FOL. Furthermore, we obtain near perfect discrimination between a protein’s native state ensemble and ensembles of misfolded structures for 55 different proteins, thereby generating far more competitive side chain packings for all of these proteins and their misfolded states.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0969-2126 ISBN Medium  
  Area Expedition Conference  
  Notes Times cited: 12 Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46310  
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