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The combined use of NMR, distance geometry, and restrained molecular dynamics for the conformational study of a cyclic somatostatin analogue
Author(s) -
Pepermans H.,
Tourwé D.,
van Binst G.,
Boelens R.,
Scheek R. M.,
van Gunsteren W. F.,
Kaptein R.
Publication year - 1988
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.360270211
Subject(s) - chemistry , molecular dynamics , nuclear overhauser effect , energy minimization , nuclear magnetic resonance spectroscopy , molecule , crystallography , cyclic peptide , stereochemistry , computational chemistry , peptide , biochemistry , organic chemistry
A cyclic peptide analogue of somatostatin, including the o ‐aminomethylphenylacetic acid spacer, was studied by the combined use of two‐dimensional nmr spectroscopy, distance geometry, and restrained molecular dynamics. Analysis of distances determined from nuclear Overhauser effect (NOE) buildup rates revealed that these were inconsistent with a unique backbone conformation near the spacer. Assuming that the conformational heterogeneity is localized to the spacer, the NOE distances measured for the remaining part of the molecule were used to generate a large number of structures with the distance geometry algorithm, which were then refined by restrained energy minimization. Four classes of structures emerged, which together account for all observed NOEs. A representative structure of each class was further refined with the restrained molecular dynamics technique, and shown to be stable on a 20‐ps time scale. The flexibility of the spacer was examined by simulating interconversions induced by an appropriate restraining potential. As a result, the explanation for the lack of somatostatin activity of the analogue studied was reconsidered.