Quiz 1: Thursday 26 Jan 2012 from 11 AM to 12 noon GG Building - - PowerPoint PPT Presentation

• Quiz 1: Thursday 26 Jan 2012

from 11 AM to 12 noon GG Building Ground Floor

• Clarification on torsion potential: periodicity 2 and 3

Conformer selection, active/inactive conformations, activation by ligands, etc. - alternative models Inter- and intra-molecular interactions Non-covalent / non-bonded interactions Bonded and non-bonded atoms Hard-sphere approximation Steric effect Preference of trans over gauche conformation for bulky groups

Last class...

• Monosubstituted cyclohexanes

Bulky group is axially

• riented: gauche to both

vicinal carbon atoms Bulky group is equatorially

• riented: trans to both

vicinal carbon atoms

• Monosubstituted cyclohexanes

Bulky group is axially

• riented: gauche to both

vicinal carbon atoms Bulky group is equatorially

• riented: trans to both

vicinal carbon atoms

• Cis 1,2-disubstituted cyclohexane

• Trans 1,4-disubstituted cyclohexane

• Unfolded

Folded (protein, DNA, RNA) Monomers (homo/hetero) Oligomer(s) (protein, lipid) A + B A·B (binding) Conformation “a” Conformation “b” ∆ ∆ ∆ ∆G = ∆ ∆ ∆ ∆H – T ∆ ∆ ∆ ∆S

What governs the conformational preferences?

Steric criterion – (approximation of) van der Waals interactions Often, van der Waals contribution is not predominant

• Conformation of 1,3,5-trineopentylbenzene

view along the plane of the ring All the three neopentyl groups are on the same side of the ring Two neopentyl groups are on one side, third on the other side of the ring Nishio & Hirota (1989) Tetrahedron 45:7201

CH2-tBu CH2-tBu tBu-H2C

• Ph-CH(Me)-X-tBu

X= CH2, CHOH, S, SO, SO2 Preferred: Tertiary butyl (tBu) group is trans to the methyl group, gauche to the phenyl group Expected solely based on steric criterion: Tertiary butyl (tBu) group is gauche to the methyl group, trans to the phenyl group gauche trans

Conformation of Ph-CH(Me)-CH2-tBu

Nishio & Hirota (1989) Tetrahedron 45:7201

• Gauche preference
• n-pentane

trans to each other

• trans to each other

Dimethoxymethane

• gauche preferred over trans

• J Chem Soc Perkin Trans. 2, (2001) 2370-3 (no volume

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Conformation of n-alkanes: chain length & solvent effect

C6D6 1-Chloronaphthalene n-Hexane Extended Extended n-Dodecane Open “U” shaped

• Steric criterion helps us to rationalize preferred

conformations only when van der Waals contribution is predominant Exceptions discussed: 1,3,5-trineopentylbenzene Ph-CHMe-CH2-tBu Dimethoxymethane – anomeric effect n-Decane in different solvents

Summary

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Relationship among monosaccharides – chemists’ view

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• Different ring forms of glucose

D-Glucose β β β β-D-Glucopyranose (4C1) α α α α-D-Glucopyranose (4C1) β β β β-D-Glucofuranose (3E) α α α α-D-Glucofuranose (3E)

• Monosaccharides: glucose, prototypical example
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• Cambridge structural database code: HEZWAK01

Rendered using RasMol 2.7.2 Caira et al., (1994) J Chem Soc Perkin Trans 2:2071

• Pyranose ring in 1C4 conformation (cyclodextrin)

• Luger et al., (1979)
• Carbohydr. Res. 68, 207

CSD refcode OBZXYP10

• Kothe et al., (1979)

Acta Cryst. B30, 365 CSD refcode OACXPF

Effect of substituents on ring conformation

Xylopyranose derivatives O-acetyl derivative O-benzoyl derivative

• Idose, an “unusual” monosaccharides

D-Glucose D-Idose

• β

β β β-D-Glucose (stereoisomer)

• Biological systems: L-enantiomer / uronic acid
• D-Idose
• L-Idose
• L-Iduronic acid

Constituent of glycosaminoglycans (e.g., heparin, heparan sulphate)

• Conformational preferences of idose

4C1-α

α α α-L-idopyranose

1C4-α

α α α-L-idopyranose

2SO-α

α α α-L-iduronopyranose

• CH2OH - axial

All 4 –OH - axial Staggered, but not maximally

Considerable fraction of monosaccharide exists in furanose form

Biochemistry by Stryer, L., p257 (2nd ed.) – heparin as anticoagulant

• Skew-boat conformation

α α α α-L-Iduronic acid (monosaccharide; aldohexose derivative) Skew-boat conformation (2SO) skew-boat conformation: atoms i and i+2 out of plane Chair / boat conformations: atoms i and i+3 out of plane

• Pyranose ring in skew-boat conformation
• Protein database id: 1SR5:NT1

Rendered using RasMol 2.7.2 In complex with antithrombin Nat Struct Mol Biol 2004 11:863

Heparin heptasaccharide

• Conformation of heparin heptasaccharide
• 1. Changes in the conformation of the pyranose rings
• 2. Rotations around the single bonds, especially those

that link the pyranose rings These will alter the spatial positions of the sulfate groups with respect to each other

Protein database id: 1SR5:NT1 Rendered using RasMol 2.7.2 In complex with antithrombin Nat Struct Mol Biol 2004 11:863

• Chair-boat transitions in polysaccharides

Polysaccharide elasticity is governed by chair-boat transitions of the glucopyranose ring

β β β β-D-Glucopyranose (4C1) α α α α-D-Glucopyranose (4C1)

Nature (1998) 396:661

Comparison of α α α α- and β β β β-linked polysaccharides

• Half-chair conformation

α α α α-D-Glucose (Glc694) part of a nonasaccharide in complex with D229N-E257Q-cyclodextringlycosyltransferase (CGTase) from Bacillus circulans strain 251 (PDB id 1CXK) Distorted towards a 2H3-half chair conformation Uitdehaag et al., (1999) Nat Struct Biol 6:432-6 atoms i and i+1 out of plane

• Ribose: in solution and in nucleic acids

β β β β-D-Ribopyranose (4C1) β β β β-D-Ribofuranose (3E)

• D-Ribose

• Distorted conformations of pyranose rings

Nature (2001) 412:835-838 Catalysis by hen egg-white lysozyme proceeds via a covalent intermediate D J Vocadlo, G J Davies, R Laine, S G Withers

Carbohydrate Research (2001) 331:461-467 Boat conformations: synthesis, NMR spectroscopy and molecular dynamics of methyl 4,6-O-benzylidene-3- deoxy-3-phthalimido-α α α α-D-altropyranoside derivatives B Coxon, R C Reynolds

Examples chosen arbitrarily