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Title
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2D-NMR and molecular dynamics analysis of the Torpedo californica acetylcholine receptor alpha 67-76 fragment and of its [Ala76]-analogue.
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Authors
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M.T.Cung,
V.Tsikaris,
P.Demange,
I.Papadouli,
S.J.Tzartos,
C.Sakarellos,
M.Marraud.
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Ref.
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Pept Res, 1992,
5,
14-24.
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PubMed id
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Abstract
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The alpha 67-76 fragment (Trp67-Asn68-Pro69-Ala70-Asp71-Tyr72 -Gly73-Gly74-
Ile75-Lys76) of the Torpedo californica acetylcholine receptor (AChR) is
selectively recognized by antibodies against the main immunogenic region of the
AChR. The antibody binding capacity of its [Ala76]-analogue is usually higher
than that of the natural fragment. A conformational analysis of these two
decapeptides has been carried out in Me2SO by 2D-NMR and molecular dynamics
using the SYBYL and BIOGROMOS programs. The natural sequence presents the most
numerous and strongest NOE connectivities and is accordingly less flexible than
the [Ala76]-analogue. Due to the flexible orientation of the side chains in both
peptides, the NOE backbone side chain and side chain-side chain connectivities
have not been introduced as distance constraints in the molecular dynamics
calculations. It appeared that the N-terminal heptapeptide in both sequences
assumes two very similar folded conformations, whereas the Ala substitution
induces conformational flexibility in the C-terminal tripeptide sequence. The
most flexible [Ala76]-analogue is the most tightly bound to the monoclonal mAb6
anti-AChR antibody, and the transferred NOEs from the bound to the free peptide
in D2O reveal some similarity with the intrinsic NOEs for the free natural
sequence in Me2SO, suggesting that the bound conformation of the
[Ala76]-analogue could not be very different from that of the free natural
fragment.
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