Folding: another kind of

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Folding another kind of supramolecular assembly?
Usually Supramolecular Chemistry considers
interactions between molecules, however folding
is a special case in which polymers have
intramolecular interactions between parts of one
molecule separated by many covalent bonds which
lead to a preferred conformation.
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types of supramolecular assembly
host / guest
exo-self-assembly
folding
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Folding another kind of supramolecular assembly?
total 3 dimensional shape of a protein is
completely determined by the sequence of amino
acids (primary structure) (excluding environment
effects such as solvent composition, temperature
pressure) how proteins transition from a
linear polymer to a folded 3 dimensional
structure is not well understood the protein
folding problem
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Secondary Structure a-helix
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Secondary Structure a-helix
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Secondary Structure a-helix
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Secondary Structure a-helix
Pro Gly His Asn Thr Val Asp Tyr Ile Cys Glu Gln
Ser Phe Trp Met Leu Lys Arg Ala
Propensity of AA to form alpha-helix
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Secondary Structure a-helix
right handed helix i and i 4 residues form
H-bonds 3.6 aa / turn 1.5Å / aa 5.4Å / turn 7-15Å
in diameter (side chain dependant) side chains
tilted toward amino end of helix has macro dipole
of 3.5D / amino acid proline breaks alpha helices
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Secondary Structure a-helix
600o
200o
300o
X
500o
700o
0o
720o
100o
400o
Helical wheel representation
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Secondary Structure a-helix helical wheel
representation
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Amino Acid Propensity for Secondary Structure
Certain amino acids prefer to be in alpha-helical
or beta sheet conformation Alanine prefers
alpha helical conformation Negatively charged
amino acids like to be at the N-terminal end of
an alpha helix Positively charged amino acids
like to be at the C-terminal end of an alpha
helix Glycine and Proline strongly destabilize
an alpha helix
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Can we synthesize a loan a-helix ?
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Can we synthesize a loan a-helix ?
C-term
d-
Helps to stabilize the charge separation of the
macro-dipole
NH3
COO-
N-term
d
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Further Improvements
NH3
COO-
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Short Peptides Do Not Fold
Using information about amino acid propensity for
forming a particular secondary structure we find
that the peptide in question only adopts the
desired conformation a small fraction of the time
while exploring a wide range of structures.
Stable structures are not seen until we have in
excess of 20 amino acids.
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The Final Solution Covalent Stabilization
C-term
d-
d-
NH3
NH3
SH
S
SH
S
COO-
COO-
N-term
d
d