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Molecular Recognition Molecular Recognition Chemical Understanding of Biological Complexity Dr. Henry Dube Supramolecular Chemistry Covalent Noncovalent Atoms Molecules Supramolecules Synthesis Molecular Interactions Molecular Assembly Molecular Recognition HNO3, NO2 H2SO4 2 From Making Substrates to Making Receptors Chemical Substrate Drug Design Natural Receptor Substrate Supramolecular Chemistry Synthetic Receptor 3 Making Substrates: Structure Based Drug Design Disease Structure Ligand Design determination Target X-Ray Crystal structure Biologically active molecules Designed Ligand Assay Synthesis Clinical Studies, Drugs Synthesized Ligand 4 From Making Substrates to Making Receptors Chemical Substrate Drug Design Natural Receptor Substrate Supramolecular Chemistry Synthetic Receptor 5 Early Supramolecular Chemistry 1967 Pedersen 1978 Lehn 1953 Freudenberg, Cramer, Plieninger Complexation of Cations Complexation of Neutral Molecules OH HO O O O OH HO OH O O HO Me CO2H O HO OH O O OH O O O K N O O N O O O O O HO OH OH Me O O O OH OH Me O OH OH OH O O Crown ether Cryptand HO α-Cyclodextrin Lehn, Angew. Chem. 1988, 100, 91. Cram, Angew. Chem. 1988, 100, 1041. Pedersen, Angew. Chem. 1988, 100, 1053. 6 Molecular Recognition: Host–Guest Chemistry Molecular Capsules Wyler, de Mendoza, Rebek, Jr., Angew. Chem. Int. Ed. 1993, 32, 1699. Kang, Rebek, Jr., Nature 1996, 382, 239. 7 Molecular Recognition: Biomimetic Chemistry Synthetic Model for Hemoglobin and Myoglobin N Distal His N H 2.97 Å 3.08 Å R N N Co N N O R N Proximal His N Dube, Kasumaj, Calle, Saito, Jeschke, Diederich, Angew. Chem. Int. Ed. 2008, 47, 2600. Dube, Kasumaj, Calle, Felber, Saito, Jeschke, Diederich, Chem. Eur. J. 2009, 15, 125. 8 Supramolecular Chemistry: Generating Complexity Stoddart and co-workers, Science 2004, 304, 1308 PDB code: 1EVE • Biology • Drug discovery - Drug design • Supramolecular Architectures • Smart Materials • Molecular Machines • ... J.-M. Lehn and co-workers, Mol. Cryst. Liq. Cryst. 2007, 468, 187 Fujita and co-workers, Angew. Chem. Int. Ed. 2011, 44, 10318 9 Introduction Synthetic Models for Cytochrome Analysisc of Binding – Binding Energy cytochrome c was resolved in 2002 by Lange et al. and gives profound insight into the stereochemical organization of the two proteins during electron transfer [190]. A distance of 9.4 Å is observed between the edge-to-edge oriented heme groups of the cytochrome c1 center and cytochrome c. The close spacial arrangement of the two heme groups suggests a direct and rapid electron transfer, the rate of which was calculated to be approximately 8.3 x 106 s-1. -ΔG = Binding Energy N N O H O O R K O O N N Co O N N O R N N 10 Figure 103 X-ray crystal structure of complex III with bound cytochrome c (PDB code: 1KYO, resolution 2.97 Å). a) Binding of cytochrome c to the homodimeric QCR. Bound cytochrome c site is encircled. b) Direct heme-to-heme electron transfer from cytochrome c1 to cytochrome c. The short edge-to-edge distance from one heme to the other is 9.4 Å. At the cytochrome oxidase the ferrous cytochrome c is oxidized to its ferric form. The electron is transferred first to CuA, a binuclear copper center, which has a higher redox potential of 290 mV vs. SHE [188]. From there, the electron is transferred through the protein to the final electron acceptor dioxygen. Cytochrome c is present in all organisms that have mitochondrial respiratory chains: plants, animals, and eukaryotic microorganisms. The protein evolved 1.5 billion years ago, before the divergence of plants and animals. Its function has been conserved until today; cytochrome c of any eukaryotic species reacts in vitro with the cytochrome c oxidase of any other species tested so far. 176 Binding Energy and Binding Constant -ΔG = R.T.lnK -ΔG = Binding Energy K = Binding Constant K = Complexed / Uncomplexed –5,7 kJ/mol ! K = 10 ! 90.1% Complexed (if conc. = 1) 11 Binding Energy and Binding Constant -ΔG = R.T.lnK -ΔG = Binding Energy K = Binding Constant K = Complexed / Uncomplexed –50 kJ/mol ! K = 109 ! 99.9999% Complexed - Nanomolar Binding 12 Intermolecular Interactions Are Dynamic 85 kJ/mol ! Available at 25 °C - G/RT Eyring Equation: k = k T/h*e Δ B 1 min Half Life = ln2/k Dynamic Processes Unless: –85 kJ/mol ! K = 1015 Femtomolar Binding 13 Intermolecular Interactions Are Dynamic Reversible Binding: –34 kJ/mol ! K = 106 ! mikromolar Binding Example: Kinase A Binding to ATP Limit to Irreversible Binding: –68 kJ/mol ! K = 1012 ! picomolar Binding Example: G Protein Binding to GTP/GDP 14 Binding Constant: What‘s In It? - Not so Easy Binding in Water -ΔG = -ΔH + TΔS -ΔG = R.T.lnK 15 Methods to Quantify Binding o Ka, ∆G ion conductivity, UV/Vis absorption, fluorescence, NMR, calorimetry. ∆Ho, T∆So Variable temperature 1H NMR, van’t Hoff analysis Titration microcalorimetry o ∆Cp Titration microcalorimetry o ( heat capacity changes = ∂(∆H )/∂T ) Note that Kd ≈ Ki = 1/Ka (supramolecular chemists use Ka, medicinal chemists Kd and Ki) 16 Methods to Quantify Binding Formation of 1:1 host (H) – guest (G) complex proceeds according to: a – sensitive nucleus on Guest free ligand concentration b – analogous nucleus in complex c – nucleus insensitive to compexation NMR titration plot for a fast equilibrating (on Job plot showing a 1:1 host – guest the NMR timescale) system complex 17 Specifics of Binding Specific Molecular Interactions – Molecular Recognition Substrate Receptor Complex O O O H O H O O H O H O 18 Molecular Recognition – Lock and Key „To use a picture I would like to say that enzyme and glucoside have to fit together like lock and key in order to exert a chemical effect on each other.“ Fischer, Ber. Dtsch. Chem. Ges. 1894, 27, 2985. Tyr169 His181 Glu409 N NH O W OH O OH W W Trp402 H O OH NH NH O HO OH 2 HO S HN O OH W HN W OH Arg W W 243 O O O O O O O HO NH2 Glu167 Glu356 Glu167 Gln316 β-Glucosidase Tyr298 Isorna, Polaina, Latorre-Garcia, Cañada, Gonzalez, Sanz-Aparicio, J. Mol. Biol. 2007, 371, 1204. 19 Molecular Recognition – Specific Interactions Complex Network of Weak Interactions Aricept® in Acetylcholinesterase – Alzheimer‘s Disease H O H Phe330 O cation–π MeO + N Trp84 MeO π–π stacking H π–π stacking H O H H Trp279 O O–H/π H Kryger, Silman, Sussman, J. Physiol. (Paris) 1998, 92, 191–194; Kryger, Silman, Sussman, Structure 1999, 7, 297–307. 20 Weak Interactions: Toolbox to Make Supramolecules 21 Hydrogen Bonds A hydrogen bond is the bonding of a covalently attached H-atom with a second atom Bond energy range: 4 – 120 kJ/mol 22 Hydrogen Bonds 23 Hydrogen Bonds Long Range Interactions: Energy scales with 1/r 24 Hydrogen Bonds Structure and Stability of H-Bonds 25 Hydrogen Bonds DNA Double and Triple Helices 26 Hydrogen Bonds Secondary Electrostatic Interactions – Important if # of H- Bonds are Identical 27 Hydrogen Bonds H H N N H O O H N N N N N N H Et N H N Et N N N N O H N Sugar Cy O H N H H C G T 2-Aminoadenine Prior to the model advanced by Jorgensen, these differences in stability between base pair associations were not understood. 28 Hydrogen Bonds When the model was developed in 1991, a DDD . AAA system was missing. It was later prepared by Zimmerman (J. Am. Chem. Soc. 1992, 114, 4010), confirming the predictions based on consideration of secondary electrostatic effects 29 Electrostatic Interactions Ion Paring (Coulombic Interactions) Coulomb Potential: 1 z+ z–·e2 U = potential energy ____ . ______ Uion-ion = – z · e = ionic charge 4π·εo ε r· r εr, εo = dielectric constant of vacuum (=1) and environment (solvent) r = distance between ions 30 Electrostatic Interactions Ion-pairing often is entropy-driven, due to solvation of the interacting ions Table. Selected thermodynamic ion-pairing parameters (kcal mol-1) at 298 °C in water. ______________________________________________________________________ Ion pair ∆G° ∆H° T∆S° ______________________________________________________________________ 2+ 2– Ca SO4 – 3.2 1.6 4.8 3+ 3– La Fe(CN)6 – 5.1 2.0 7.1 ______________________________________________________________________ • Free enthalpy contribution of non-buried salt bridges: 1.25 ± 0.25 kcal mol-1 H. J. Schneider et al. Chem. Soc. Rev. 1994, 23, 227 31 Electrostatic Interactions Ion – Dipole Interactions (50 – 200 kJ/mol) 1 z · e · µ · cos θ εo = dielectric constant ____ __________________ Uion-dipole = – · z · e = ionic charge 2 4 π εo r r = distance between centers of ion and dipole µ = dipole moment θ = angle between dipole and line r. O H H O O O r K ϑ K O O O 32 Ion Dipole Interactions at Work O R R O O O O O O R R N O O N O O O O O O O O O O Me R O O O 33 Ion Dipole Interactions at Work – Ion Channels Compare 8-fold coordination by valinomycin and 6-fold Coordination by nonactin The selectivity filter of the K+ channel depicted as five sets of four-in-plane O-atoms with K+ ions (green) undergoing cubic coordination to eight protein C=O groups in the 1,3- and 2,4-configurations. Movement by two paths involves octahedral coordination by six O-atoms, two provided by the intervening H2O molecules. 34 Electrostatic Interactions Dipole – Dipole Interactions (5 – 50 kJ/mol) 35 Electrostatic Interactions The potential energy of interaction between two polar molecules is a complicated function of the angle between them. However, when the two dipoles are parallel or aligned towards each other, the energy between stationary polar molecules is f µ1 · µ2 µ = dipole moment _____ ____________ 2 Udipole-dipole = · f = 1 – 3 cos θ 3 (4 π ·εo ) r There is a non-zero average interaction between freely rotating dipoles.
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