Bulletin of the American Physical Society
2006 APS March Meeting
Monday–Friday, March 13–17, 2006; Baltimore, MD
Session K29: Proteins Structure and Function |
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Sponsoring Units: DBP Chair: F. A. Ferrone, Drexel University Room: Baltimore Convention Center 326 |
Tuesday, March 14, 2006 2:30PM - 2:42PM |
K29.00001: Biochemical Reversal of Aging John T.A. Ely We cite our progress on biochemical reversal of aging. However, it may be circa 2 years before we have necessary substances at low cost. Meanwhile, without them, a number of measures can be adopted providing marked improvement for the problems of aging in modern societies. For example, enzymes are needed to excrete toxins that accelerate aging; Hg is the ultimate toxin that disables all enzymes (including those needed to excrete Hg itself). Low Hg level in the urine, due to loss of excretory ability, causes the diagnosis of Hg toxicity to almost always be missed. Hg sources must be removed from the body! Another example is excess sugar; hyperglycemia decreases intracellular ascorbic acid (AA) by competitively inhibiting the insulin- mediated active transport of AA into cells. Thus, immunity is impaired by low leucocyte AA. AA is needed for new proteins in aging tissues. Humans must supplement AA; their need same as in AA-synthesizing mammals. [Preview Abstract] |
Tuesday, March 14, 2006 2:42PM - 2:54PM |
K29.00002: A Unified Approach to Sickle Hemoglobin Gelation and Phase Separation F.A. Ferrone, M.U. Palma, M.B. Palma-Vittorelli Protein aggregation has been identified as a major component in a number of diseases of which the earliest known and most thoroughly studied is sickle cell disease. Because of its direct bearing on pathophysiology, HbS polymer formation has been extensively described. The principal challenge now lies in the need of reconciling well documented but apparently contrasting properties of HbS solutions. These are the purely hard-sphere behavior of HbS under non-gelling conditions (extending to the 7th order in virial coefficients), and the equally well documented existence of a region of liquid-liquid demixing of the solution, from which notable deviations from hard-sphere behavior would be expected. We present a strategy to circumvent this impasse by including explicit and well known activity coefficients in a Flory-Huggins like term in the monomer chemical potential. This preserves the successful thermodynamic treatment of polymer formation while introducing a term leading to a spinodal. The formulation is consistent with known data, and implications for kinetics will be described. [Preview Abstract] |
Tuesday, March 14, 2006 2:54PM - 3:06PM |
K29.00003: Fluorescence photocycle of GFP studied by trapping phototransformation intermediates Georgi Georgiev, Timothy Sage, Jasper van Thor The fluorescence photocycle consists involves excited state proton transfer (ESPT) from chromophore to Glu222, ionizing chromophore and neutralizing Glu222. A competing low quantum yield phototransformation process ionizes chromophore, and decarboxylates Glu222. We report spectroscopic measurements on cryotrapped reaction intermediates of the phototransformed GFP that electrostatically mimic intermediates in the fluorescence photocycle. Illumination at 100K leads to appearance of both a visible absorption band at 497nm, indicating an ionized chromophore in a non-equilibrium environment, and of multiple IR bands due to photogenerated carbon dioxide, confirming the decarboxylation of Glu222. Additional changes in the IR spectrum reflect numerous rearrangements of surrounding side chains and internal water molecules even at 100K. Polarized IR measurements on single crystals, measurements on mutant GFP, and solvent exchange measurements allow us to identify IR difference signals due to Gln69, Cys70, and weakly hydrogen-bonded internal water molecules. These spectroscopic changes highlight the role of the chromophore environment in preventing nonradiative decay of the excited state, and thereby enhancing the quantum efficiency. [Preview Abstract] |
Tuesday, March 14, 2006 3:06PM - 3:18PM |
K29.00004: Mechanisms of triggering H1 helix in prion proteins unfolding revealed by molecular dynamic simulation Chih-Yuan Tseng, H.C. Lee In template-assistance model, normal Prion protein (PrP$^{\textnormal{C}}$), the pathogen to cause several prion diseases such as Creutzfeldt-Jakob (CJD) in human, Bovine Spongiform Encephalopathy (BSE) in cow, and scrapie in sheep, converts to infectious prion (PrP$^{\textnormal{Sc}}$) through a transient interaction with PrP$^{\textnormal{Sc}}$. Furthermore, conventional studies showed S1-H1-S2 region in PrP$^{\textnormal{C}}$ to be the template of S1-S2 $\beta$-sheet in PrP$^{\textnormal{Sc}}$, and Prion protein's conformational conversion may involve an unfolding of H1 and refolding into $\beta$-sheet. Here we prepare several mouse prion peptides that contain S1-H1-S2 region with specific different structures, which are corresponding to specific interactions, to investigate possible mechanisms to trigger H1 $\alpha$-helix unfolding process via molecular dynamic simulation. Three properties, conformational transition, salt-bridge in H1, and hydrophobic solvent accessible surface (SAS) are analyzed. From these studies, we found the interaction that triggers H1 unfolding to be the one that causes dihedral angle at residue Asn$^{\textnormal{143}}$ changes. Whereas interactions that cause S1 segment's conformational changes play a minor in this process. These studies offers an additional evidence for template-assistance model. [Preview Abstract] |
Tuesday, March 14, 2006 3:18PM - 3:30PM |
K29.00005: Analyzing knots in protein structures Peter Virnau, Mehran Kardar, Leonid Mirny Although globular homopolymers display an abundance of knots (Virnau et al, J. Am. Chem. Soc. 127, 15102 (2005)), only about one in a thousand protein structures are knotted. Can this absence of entanglement be explained in terms of statistical mechanics or is there an evolutionary bias? Do knots in proteins serve a purpose and how do they actually fold? To elaborate on this, we will present an overview of knotted proteins from the current version of the Protein Data Bank. We will also discuss some particularly intriguing examples of this set. [Preview Abstract] |
Tuesday, March 14, 2006 3:30PM - 3:42PM |
K29.00006: Designing novel kinases using evolutionary sequence analysis Areez Mody, Joan Weiner, Lakshman Iyer, Sharad Ramanathan Cellular pathways with new functions are thought to arise from the duplication and divergence of proteins in existing pathways. The MAP kinase pathways in eukaryotes provide one example of this. These pathways consist of the MAP kinase proteins which are responsible for evoking the correct response to external stimuli. In the yeast {\it Saccharomyces cerevisiae} these pathways detect pheromones, osmolar stresses and nutrient levels, leading the cell into dramatic changes of morphology. Despite being homologous to each other, the MAP kinase proteins show specificity of function. We investigate the nature of the amino acid sequences conferring this specificity. To this end, we i) search the sequences of similar proteins in other Eukaryote species, ii) make a study of simple theoretical models exploring the constraints felt by these protein segments and iii) experimentally construct, a large suite of hybrid proteins made of segments taken from the homologous proteins. These are then expressed in Yeast cells to see what function they are able to perform. Particularly we also ask whether it is possible to design a new kinase protein possessing new function and specificity. [Preview Abstract] |
Tuesday, March 14, 2006 3:42PM - 3:54PM |
K29.00007: Phase Diagram for Urate Oxidase Nathaniel Wentzel, James D. Gunton Urate Oxidase from \textit{Asperigillus flavus} has been shown to be a model protein in terms of understanding the effects of PEG on the crystallization of large proteins. Extensive experimental studies based on SAXS (Vivares et al, J. Phys. Chem. B 108, 6498 (2004)) have determined the effects of salt, pH, temperature, and most importantly polyethylene glycol (PEG), on the crystallization of this protein. Recently, some aspects of the phase diagram have also been determined. In this paper we use Monte Carlo techniques to predict phase diagrams for urate oxidase in solution with PEG. The model used includes an electrostatic interaction, van der Waals attraction, and a polymer-induced depletion interaction (Vivares et al, Eur. Phys. J. E 9, 15 (2002)). Results of the simulation are compared with experimental results. [Preview Abstract] |
Tuesday, March 14, 2006 3:54PM - 4:06PM |
K29.00008: Inter-Domain Dynamics in a Two-Domain Protein Studied by NMR Yaroslav Ryabov, David Fushman Domain orientation and dynamics often play an important role in regulation of multidomain proteins function. Here we consider a two-domain system, Lys48-linked di-ubiquitin (Ub$_{2})$, which is the simplest model of the polyubiquitin chain involved in the ubiquitin-proteasome pathway. Under physiological conditions Ub$_{2}$ adopts a compact conformation, in which the functionally important hydrophobic residues are sequestered at the interface between the two Ub$_{2}$ domains. Here we present a dynamic model that combines the anisotropic overall rotational diffusion with intra- and interdomain dynamics. This model describes the interdomain motion as a transition between two distinct conformational states. The model is applied to experimental $^{15}$N relaxation data for Lys48-linked Ub$_{2}$ acquired at neutral (pH 6.8) and acidic (pH 4.5) conditions. The model provides complete picture of Ub$_{2}$ domain mobility including domain orientations, time scales of domain motions, and occupation probabilities for both states of Ub$_{2}$. The obtained results are consistent with independent data on chemical shift perturbation mapping and spin labeling. [Preview Abstract] |
Tuesday, March 14, 2006 4:06PM - 4:18PM |
K29.00009: Discovering the recognition code bacteria use to sense their environment by tracking co-evolutionary patternsBacteria typically posses tens of distinct signaling pathways that allow the organism to translate diverse environmental conditions into action Robert White, Terry Hwa, Jim Hoch Bacteria typically posses tens of distinct signaling pathways that allow the organism to translate diverse environmental conditions into action. A common signaling mechanism is a bucket brigade of phosphate triggered by the auto-phosphorylation of ``sensor kinase'' (SK) then passed to a protein called a ``response regulator'' (RR). The phosphorylation state of the RR regulates its function, thereby completing the signaling pathway. In one organism---but in pathways responsible for sensing diverse signals---the domains at which the transfer of the phosphate group occurs show surprising homology to each other. What keeps the organism from getting its signals crossed? We present a detailed bioinformatic study of over 1500 cognate SK/RR pairs that reveals patterns that can be used to predict the presence of evolved crosstalk and shed light on the paralogous divergence of these essential messengers. [Preview Abstract] |
Tuesday, March 14, 2006 4:18PM - 4:30PM |
K29.00010: Simple Model of Sickle Hemoglobin Andrey Shiryayev, Xiaofei Li, James Gunton A microscopic model is proposed for the interactions between sickle hemoglobin molecules based on information from the protein data bank. A Monte Carlo simulation of a simplified two patch model is carried out, with the goal of understanding fiber formation. A gradual transition from monomers to one dimensional chains is observed as one varies the density of molecules at fixed temperature, somewhat similar to the transition from monomers to polymer fibers in sickle hemoglobin molecules in solution. An observed competition between chain formation and crystallization for the model is also discussed. The results of the simulation of the equation of state are shown to be in excellent agreement with a theory for a model of globular proteins, for the case of two interacting sites. [Preview Abstract] |
Tuesday, March 14, 2006 4:30PM - 4:42PM |
K29.00011: Antifreeze Protein Binds Irreversibly to Ice I. Braslavsky, N. Pertaya, C.L. Di Prinzio, L. Wilen , E. Thomson, J.S. Wettlaufer, C.B. Marshall, P.L. Davies Many organisms are protected from freezing by antifreeze proteins (AFPs), which bind to ice and prevent its growth by a mechanism not completely understood. Although it has been postulated that AFPs would have to bind irreversibly to arrest the growth of an ice crystal bathed in excess liquid water, the binding forces seem insufficient to support such a tight interaction. By putting a fluorescent tag on a fish AFP, we were able to visualize AFP binding to ice and demonstrate, by lack of recovery after photo-bleaching, that it is indeed irreversible. Because even the most avid protein/ligand interactions exhibit reversibility, this finding is key to understanding the mechanism of antifreeze proteins, which are becoming increasingly valuable in cryopreservation and improving the frost tolerance of crops. [Preview Abstract] |
Tuesday, March 14, 2006 4:42PM - 4:54PM |
K29.00012: Fluorescence microscopy studies of the hyperactive antifreeze protein from an insect N. Pertaya, C.L. Di Prinzio, L. Wilen, E. Thomson, J.S. Wettlaufer, C.B. Marshall, P.L. Davies, I. Braslavsky Antifreeze proteins (AFPs) protect animals from freezing by binding to extracellular ice and inhibiting its growth. Since the initial discovery of AFPs in fish, non-homologous types have been found in insects, plants, bacteria, fungi, and vertebrates. Different AFP types have diverse structures and varied activities. For example, AFPs produced by insects are much more active in inhibiting ice crystal growth compared to most AFPs found in fish or plants. By putting a fluorescent tag on an insect AFP we were able to visualize AFP binding to ice, to determine the ice crystal surfaces to which the AFP adheres, and to follow the kinetics of AFP binding to ice. We expect this approach will contribute to a better understanding of the mechanism of AFP activity and in particular the hyperactivity of insect AFPs. [Preview Abstract] |
Tuesday, March 14, 2006 4:54PM - 5:06PM |
K29.00013: Self-assembly of type 1 collagen : Interaction between normal and mutant collagen Sejin Han, Wolfgang Losert We investigate the self-assembly of type 1 collagen, termed fibrillogenesis. Fibrillogenesis of type I homozygous mutations revealed a substantial difference in the kinetics, in particular, rapid growth of fibers and the absence of lag time. We developed a technique for differential fluorescent labeling of collagen combined with laser scanning confocal microscopy for time dependent observation of fibrillogenesis kinetics and structural properties in 3D. We observed that co-assembly of heterotrimers (normal) and homotrimers (mutant) in mixtures within the same fibrils during fibrillogenesis, despite their very different fibrillogenesis kinetics. Turbidity measurements of fibrillogenesis of mixture of hetero- and homotrimers showed the normal S-shaped curve with a lag time typical of heterotrimers. We characterized the structural topology of the collagen 3D network through Betti numbers that are primarily describing the connections between different components. We found that homotrimers has fewer intersections per disjoint fiber than normal heterotrimers, demonstrating finer and straighter network structure in images. ~ [Preview Abstract] |
Tuesday, March 14, 2006 5:06PM - 5:18PM |
K29.00014: MutY: optimized to find DNA damage site electronically? Jong-Chin Lin, Daniel Cox, Rajiv Singh Iron sulfur clusters are present in the DNA repair protein MutY in a region highly homologous in species as diverse as $E.$ $Coli$ and Homo Sapiens, yet their function remains unknown. In MutY, this mixed valence cluster exists in two oxidation states, [Fe$_{4}$S$_{4}$]$^{2+/3+}$, with the stability depending upon the presence of DNA. We have studied the electronic structure and stability of these clusters using the local orbital based SIESTA implementation of density functional theory. We find that the iron-sulfur cluster in MutY can undergo 2+ to 3+ oxidation when coupling to DNA through hole transfer, especially when MutY is near an oxoguanine modified base(oxoG). Employing the Marcus theory for electron transfer, we find (i) near optimal Frank-Condon(FC) factor for 2+ transfer to oxoG; (ii) reduced FC factor for transfer to G due to a high oxidation potential; (iii) reduced FC factor with the mutation L154F; (iv) reduced tunning matrix element with the mutation R149W. Both L154F and R149W mutations dramatically reduce or eliminate repair efficiency. Hence, redox modulation of MutY search and binding appears plausible and may have broader implications for DNA-protein interactions. [Preview Abstract] |
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