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Protein-carbohydrate recognition phenomena illustrated through simulation and thermodynamic calculations

Christina M. Payne, Department of Chemical and Materials Engineering, ÌÇÐÄvlog¹Ù·½Èë¿Ú, Lexington, KY

Carbohydrates are the most abundant biological molecules on Earth and play important roles in metabolism, cell wall structure, and cellular-level processes; they also happen to be one of the most structurally diverse natural substrates, constructed from a variety of chemically distinct monosaccharides and glycosidic linkages. In response to this diversity, carbohydrate-binding proteins have evolved many different structural approaches to enable recognition of complex carbohydrate substrates. Molecular simulation and free energy calculations, coupled with structural and biochemical observations, can provide extraordinary resolution of molecular-level protein-carbohydrate recognition mechanisms. In this talk, I describe two recent studies wherein we used molecular modeling to reveal the underpinnings of experimentally-observed protein-carbohydrate recognition phenomena. In the first example, we will examine the recognition mechanisms of b-sandwich carbohydrate binding modules (CBMs), a non-catalytic domain of carbohydrate-active enzymes. Counterintuitively, our results suggest these CBMs accommodate cello-oligomers in a bi-directional fashion, and the approximate structural symmetry of the substrate enables such promiscuity. In the second example, we will look at the substrate recognition mechanisms of a mammalian glycoprotein and biomarker, YKL-40, associated with chronic inflammatory diseases and a multitude of cancers. Identification of the lectin’s physiological ligand and biological function has proven experimentally difficult. Using a multifaceted computational approach, we evaluated the feasibility of binding several different polysaccharide and collagen peptide ligands; hyaluronan was revealed as the likely physiological ligand, consistent with associated in vivo expression levels. In general, our approaches reveal valuable fundamental insights into the complex solid and soluble carbohydrate substrate recognition mechanisms of biomolecules, the findings of which hold considerable promise in advancing lignocellulosic biotechnology, glycome mapping tools, and pharmaceutical antagonist design.

Paul Fitzpatrick, Department of Biochemistry and Structural Biology

University of Texas at San Antonio

Structural Basis for Regulation and Specificity in the Aromatic Amino Acid Hydroxylases

The non-heme iron-containing enzymes tyrosine hydroxylase and phenylalanine hydroxylase catalyze the hydroxylation of the aromatic side chains of their respective substrates. Phenylalanine hydroxylase initiates the catabolism of excess phenylalanine in the diet; a deficiency in the enzyme results in the disease phenylketonuria. Tyrosine hydroxylase catalyzes the rate-limiting step in the biosynthesis of the catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine. The catalytic domains of the two enzymes have very similar structures, and detailed studies of the catalytic mechanisms have established that both enzyme utilize the same mechanism. Mutagenesis of Asp425 in tyrosine hydroxylase converts the enzyme to a highly efficient phenylalanine hydroxylase. Saturation mutagenesis of this residue has provided insight into the basis for this change in specificity.

The sequences of their N-terminal regulatory domains differ significantly, consistent with divergent regulatory mechanisms. Tyrosine hydroxylase is regulated by a balance between feedback inhibition and phosphorylation, while phenylalanine hydroxylase is allosterically regulated by phenylalanine. Using a combination of structural approaches we have determined the structural basis for the regulation of the two enzymes, showing that a common structural fold underlies discrete regulatory mechanisms.

Atomic Layer Deposition Methods for Future Textile Electronic Systems

Advanced materials processing methods provides the opportunity for next-generation flexible electronics such as a textile fabric.  This presentation will review activity in the NEXT (Nano-Extended Textiles) research group at NC State, focused on the use of engineering design principles to develop integration and materials strategies of electronics in textiles that include new techniques that enable future industrial growth.  To this end, atomic layer deposition (ALD) and ALD-related vacuum-based processes, typically used for nanoscale materials growth in microelectronics, are defined for polymer films and fabrics.  Of particular interest is development of a new technique, called sequential vapor infiltration (SVI), by which organometallic ALD precursors are infiltrated into the bulk polymer materials and react with the available functional sites to form a network of organic / inorganic hybrid materials. The unique electro-optical properties of these hybrid materials will be explored, which opens a door to new patterned processing methods for textile electronic interconnects and sensors.       

Bio:

Dr. Jesse Jur is an Assistant Professor of Textile Engineering, ÌÇÐÄvlog¹Ù·½Èë¿Ú & Science at NC State University's College of Textiles, the global leader in textile education and research. After his undergraduate studies at the University of South Carolina and industrial experience in Silicon Valley, Dr. Jur earned his Ph.D. in Materials Science and Engineering at NC State in 2007. Dr. Jur’s studies examine the interfaces of technologies from semiconductor device development to textile designs.  His current research focuses on integration of systems electronics into wearable platforms for energy harvesting and monitoring of a person's environmental and physiological state. He is the Technology Thrust Leader for ‘Wearability and Data’ for ASSIST (Advanced Self-Powered Systems of Integrated Sensors and Technologies), a National Science Foundation Nanosystems Engineering Research Center (NERC).  He is also the co-director of the Textile Engineering and Textile Technology Engineering Design Program in the College of Textiles, an intensive course that interfaces students and industry for innovative product development.

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Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway.

TITLE:  Seeking a plausible prebiotic solution (and solvent) for the origin of RNA 

ABSTRACT:  The RNA World remains a popular and influential hypothesis in origins of life research. However, prebiotic chemists are still lacking a plausible prebiotic synthesis for RNA. We are investigating the possibility that RNA was preceded by a polymer that would have assembled more easily than RNA (i.e., pre-RNA), and that non-aqueous solvents could have facilitated prebiotic nucleic acid synthesis and replication. In support of these theories, recent experiments have revealed alternative nucleobases that readily form nucleosides with ribose, a property not observed with the nucleobases of extant RNA. Alternative solvents have also been identified that allow nucleoside phosphorylation from water-insoluble minerals, as well as the polymerase-free transfer of information from long nucleic acid duplexes.

Abstract:

Proteins are intrinsically dynamic. By undergoing motions on a wide range of time and length scales, they are able to bind substrates, regulate their own activities, and transmit information over considerable distances. In this talk, I will discuss multiple projects in our group that utilize conventional and enhanced sampling molecular dynamics simulations to probe these dynamical properties for a diverse array of systems. Our results reveal atomic-scale details about how seemingly minor protein modifications can influence molecular motions and interactions and, by working closely with our experimental collaborators, help to discern the molecular mechanisms of biomolecular complexes.

METAL OXIDE NANOSTRUCTURES FOR ELECTRONICS AND ENERGY APPLICATIONS: ENDOWING "INTELLIGENCE" THROUGH PHASE TRANSFORMATIONS

Scaling ceramics and metals to nanoscale dimensions substantially alters their phase stabilities and phase diagrams with tremendous consequences for the manifestation of unique physical phenomena. Such new physical phenomena that oftentimes have no parallels in the bulk can be utilized to fabricate novel functional materials with applications for logic circuitry, "smart windows", photocatalysis, and electrochemical energy storage. In this talk, I will focus on our recent results on the influence of finite size and doping on the metal-insulator phase transitions of the binary vanadium oxide VO₂. We have achieved substantial tunability of the critical transition temperature between -20 and 70°C through control of dimensionality, morphology, and dopant concentration in hydrothermally prepared single-crystalline VO₂ nanostructures. The tunability of the phase diagram portends applications of these materials as dynamically switchable glazings for energy efficient windows (smart windows!). I will further discuss colossal metal—insulator switching recently discovered in M_xV₂O₅ bronze phases, platforms for photocatalysis that exploit the tunabilty of the band structure within these compounds, and the interplay between structure and chemical bonding for intercalation of Li and Mg-ions within V₂O₅ and the implications therein for novel battery architectures.

Keywords: smart windows, phase transformations, vanadium oxides

References:

1) K. E. Pelcher, C. C. Milleville, L. Wangoh, S. Chauhan, M. R. Crawley, L. F. J. Piper, D. F. Watson, and S. Banerjee, Integrating β-Pb_0.33V₂O₅ Nanowires with CdSe Quantum Dots: Towards Nanoscale Heterostructures with Tunable Interfacial Energetic Offsets, ÌÇÐÄvlog¹Ù·½Èë¿Ú of Materials 2015, 27, 2468-2479.

2) P. M. Marley, G. A. Horrocks, K. E. Pelcher, and S. Banerjee, Transformers: The Changing Phases of Low-Dimensional Vanadium Oxide Bronzes, Chemical Communications 2015, 51, 5181-5198.

3) P. M. Marley, T. A. Abtew, K. E. Farley, G. A. Horrocks, R. V. Dennis, P. Zhang, and S. Banerjee, Emptying and Filling a Tunnel Bronze, Chemical Science 2015, 6, 1712-1718.

4) G. A. Horrocks, S. Singh, M. F. Likely, G. Sambandamurthy, S. Banerjee, Scalable Hydrothermal Synthesis of Free-Standing VO₂ Nanowires in the M1 Phase, ACS Applied Materials and Interfaces 2014, 6, 15726-15732.

5) P. M. Marley, S. Singh, T. A. Abtew, C. Jaye, D. A. Fischer, P. Zhang, G. Sambandamurthy, S. Banerjee, Electronic Phase Transitions of δ-Ag_xV₂O₅ Nanowires: The Interplay between Geometric and Electronic Structure, Journal of Physical ÌÇÐÄvlog¹Ù·½Èë¿Ú C 2014, 118, 21235–21243.