Proceedings - Interdisciplinary Center for Nanotoxicity

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26 Conference on Current Trends in Computational Chemistry 2009 An Analysis of MMB‐4 Reactivating Cholinesterases Inhibited by Nerve Agents Manikanthan Bhavaraju and Steven R. Gwaltney Department of Chemistry, Center for Environmental Health Sciences, and HPC 2 Center for Computational Sciences, Mississippi State University, Mississippi State, MS 39762 MMB‐4 (1, 1’‐methylene‐bis [(4‐hydroxyiminomethyl) pyridinium] dichloride can reactivate the enzymes acetylcholinesterase (AChE) and butrylcholinesterase (BChE) when they have been inhibited by a nerve agent such as sarin and tabun. AChE hydrolyzes the neurotransmitter acetylcholine (ACh) into acetic acid and choline. The nerve agent inhibits the active site of the enzyme by phosphonylating the active site serine, which prevents the breakdown of the ACh. MMB‐4 reacts with the nerve agent and removes it, reactivating the enzyme. In order to study the role of MMB‐4 as a reactivator, its interactions with the enzymes AChE and BChE and the nerve agents sarin and tabun were modeled. An AM1 conformation analysis for MMB4 was performed using Spartan’06. In order to generate atomic charges consistent with the AMBER ff99 force field, the lowest energy conformers were optimized using Hartree‐Fock and the 6‐31G* basis set. RESP electrostatic potential charges were generated from the HF/6‐31G* calculations on the lowest energy conformer. Using Autodock 4, MMB‐4 was then docked in to the active site of AChE and BChE, along with AChE and BChE inhibited with sarin and AChE and BChE inhibited with tabun. Starting from the most appropriate docked structure, molecular dynamics simulations using explicit solvent method was carried out for each of the six systems. The simulations were run for at least 10 ns using AMBER 8 and the ff99 force field. In this poster we present an analysis of the MD simulations.
Conference on Current Trends in Computational Chemistry 2009 Predictive Catalysis Based on the Activation Strain Model Matthias Bickelhaupt Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling, Scheikundig Laboratorium der Vrije Universiteit, De Boelelaan 1083, NL1081 HV Amsterdam, The Netherlands fm.bickelhaupt@few.vu.nl Reactivity is one of the central issues, if not the core business, of chemistry. Yet, our understanding of chemical reactivity, in particular, the height of reaction barriers, still lags behind the minute understanding that we have today of molecular structure and stability. What is missing is a general model that provides physical insight into why a particular reaction has a higher or lower barrier than another (competing) reaction. Here, we present the Activation Strain model (or Activation Strain/TS Interaction model) which aims at providing such insight into chemical reactivity, in terms of the reactants. In the Activation Strain model, the potential energy surface ∆E(ζ) along the reaction coordinate ζ is decomposed into the strain energy ∆Estrain(ζ) associated with the geometrical deformation that the reactants undergo, plus the interaction energy ∆Eint(ζ) between the deformed reactants: ∆E(ζ) = ∆Estrain(ζ) + ∆Eint(ζ). Figure 1. Activation‐Strain analysis of palladium‐catalyzed C–H versus C–C bond activation. In this talk, various phenomena and tuning parameters in catalytic bond activation are addressed. What determines the course of oxidative addition via direct insertion or an SN2 pathway? Why is activation of the weaker C–C bond more difficult than that of the stronger C– H bond? (The clue is contained in Figure 1). And how does catalytic activity vary in general as one varies along different carbon‐element C–X bonds? The main focus of this talk will however be on the nature of the bite angle in catalysts with bridged biphosphine ligands. It will be shown that, at variance with common text book knowledge, the mechanism behind bite angle tuning is primarily steric (i.e., steric hindrance between ligands and substrate) and not so much electronic (i.e., d orbital energies tuned by ligand orbitals). Literature 1. W.‐J. van Zeist, R. Visser, F. M. Bickelhaupt, Chem. Eur. J. 2009, 15, 6112. 2. A. P. Bento, F. M. Bickelhaupt, J. Org. Chem. 2008, 73, 7290. 3. G. Th. de Jong, F. M. Bickelhaupt, ChemPhysChem 2007, 8, 1170. 4. M. A. van Bochove, M. Swart, F. M. Bickelhaupt, J. Am. Chem. Soc. 2006, 128, 10738. 5. F. M. Bickelhaupt, J. Comput. Chem. 1999, 20, 114. 27
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Proceedings - Interdisciplinary Center for Nanotoxicity

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