��������������� Quiz 1: Thursday 26 Jan 2012 from 11 AM to 12 noon GG Building Ground Floor
��������������� Last class... � 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
��������������� Monosubstituted cyclohexanes �� �� Bulky group is axially Bulky group is equatorially oriented: gauche to both oriented: trans to both vicinal carbon atoms vicinal carbon atoms
��������������� Monosubstituted cyclohexanes �� �� Bulky group is axially Bulky group is equatorially oriented: gauche to both oriented: trans to both vicinal carbon atoms vicinal carbon atoms
��������������� Cis 1,2-disubstituted cyclohexane �� � � � �� � � �
��������������� Trans 1,4-disubstituted cyclohexane � � � �� �� � � �
��������������� What governs the conformational preferences? Conformation “a” Conformation “b” Unfolded Folded (protein, DNA, RNA) Monomers (homo/hetero) Oligomer(s) (protein, lipid) A + B A·B (binding) ∆ G = ∆ ∆ H – T ∆ ∆ S ∆ ∆ ∆ ∆ ∆ ∆ ∆ Steric criterion – (approximation of) van der Waals interactions Often, van der Waals contribution is not predominant
��������������� Conformation of 1,3,5-trineopentylbenzene CH 2 -tBu tBu-H 2 C CH 2 -tBu Two neopentyl groups are on one side, All the three neopentyl groups are on third on the other side of the ring the same side of the ring view along the plane of the ring Nishio & Hirota (1989) Tetrahedron 45:7201
��������������� Conformation of Ph-CH(Me)-CH 2 -tBu Ph-CH(Me)-X-tBu gauche X= CH 2 , CHOH, S, SO, SO 2 Preferred: Tertiary butyl (tBu) group is trans to the methyl group, trans 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 Nishio & Hirota (1989) Tetrahedron 45:7201
��������������� Gauche preference n -pentane �� � ��� � ��� � ��� � ��� � �� � ��� � ��� � ��� � ��� � trans to each other trans to each other Dimethoxymethane �� � ����� � ����� � gauche preferred over trans
��������������� Conformation of n -alkanes: chain length & solvent effect C 6 D 6 1-Chloronaphthalene n -Hexane Extended Extended n -Dodecane Open “U” shaped J Chem Soc Perkin Trans. 2, (2001) 2370-3 (no volume #)
��������������� Summary 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
��������������� Relationship among monosaccharides – chemists’ view ��� -���� �� ���� � � �� . ��#�������'#�� ��� ��� (���� �� ���� � ���� � &� �'����� &�#�'���� ��� ��� ��� ��� ���� � ���� � ���� � ���� � � )'���"$� � !��� ���! ���� "#���� $#%��� ��� ��� ��� ��� ��� ��� ��� ��� �$$ �$��� ��� �$���# ��*� �+, �� ���� � ���� � ���� � ���� � ���� � ���� � ���� � ���� � ��$��� ���*� ������ ������� ������� ������� ������ ����� ��������� ������
��������������� Different ring forms of glucose α -D-Glucopyranose ( 4 C 1 ) α α α α -D-Glucofuranose ( 3 E ) α α α D-Glucose β -D-Glucopyranose ( 4 C 1 ) β β β β -D-Glucofuranose ( 3 E ) β β β
��������������� Monosaccharides: glucose, prototypical example � � � � � � � � � � � � /#�������� �)����0��,�� ��1� � � � /#�������� �)����0��,�� ��1� � � �
��������������� Pyranose ring in 1 C 4 conformation (cyclodextrin) �� �� �� �� �� �� Cambridge structural database code: HEZWAK01 Rendered using RasMol 2.7.2 Caira et al., (1994) J Chem Soc Perkin Trans 2:2071
��������������� Effect of substituents on ring conformation Xylopyranose derivatives CSD refcode OACXPF �� �� CSD refcode �� OBZXYP10 �� �� Luger et al., (1979) Carbohydr. Res. 68, 207 Kothe et al., (1979) �� Acta Cryst. B30, 365 �� �� �� O-acetyl derivative �� O-benzoyl derivative
��������������� Idose, an “unusual” monosaccharides ��� ��� � �� �� � �� � � �� � �� �� � � �� � �� �� � �� �� � �� D-Glucose D-Idose (stereoisomer) β β β β -D-Glucose
��������������� 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 4 C 1 - α 1 C 4 - α 2 S O - α α α -L-idopyranose α α -L-idopyranose α α α α α -L-iduronopyranose -CH 2 OH - 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 skew-boat conformation: atoms i and i+2 out of plane α α -L-Iduronic acid α α (monosaccharide; aldohexose derivative) Skew-boat conformation ( 2 S O ) Chair / boat conformations: atoms i and i+3 out of plane
��������������� Pyranose ring in skew-boat conformation �� �� �� �� Heparin heptasaccharide �� �� Protein database id: 1SR5:NT1 Rendered using RasMol 2.7.2 In complex with antithrombin Nat Struct Mol Biol 2004 11:863
��������������� Conformation of heparin heptasaccharide Protein database id: 1SR5:NT1 Rendered using RasMol 2.7.2 In complex with antithrombin Nat Struct Mol Biol 2004 11:863 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
��������������� Chair-boat transitions in polysaccharides Polysaccharide elasticity is governed by chair-boat transitions of the glucopyranose ring Comparison of α α - and β α α β β β -linked polysaccharides α -D-Glucopyranose ( 4 C 1 ) β -D-Glucopyranose ( 4 C 1 ) α α α β β β Nature (1998) 396:661
��������������� Half-chair conformation atoms i and i+1 out of plane 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 2 H 3 -half chair conformation Uitdehaag et al., (1999) Nat Struct Biol 6:432-6
��������������� Ribose: in solution and in nucleic acids ��� � �� β -D-Ribofuranose ( 3 E ) β β β � �� � �� �� � ��� D-Ribose β -D-Ribopyranose ( 4 C 1 ) β β β
��������������� 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 -D-altropyranoside derivatives α α B Coxon, R C Reynolds Examples chosen arbitrarily
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