Investigation of glucose binding sites on insulin.

Details

Serval ID
serval:BIB_5E989C2ACB4B
Type
Article: article from journal or magazin.
Collection
Publications
Title
Investigation of glucose binding sites on insulin.
Journal
Proteins
Author(s)
Zoete V., Meuwly M., Karplus M.
ISSN
1097-0134 (Electronic)
ISSN-L
0887-3585
Publication state
Published
Issued date
15/05/2004
Peer-reviewed
Oui
Volume
55
Number
3
Pages
568-581
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Possible insulin binding sites for D-glucose have been investigated theoretically by docking and molecular dynamics (MD) simulations. Two different docking programs for small molecules were used; Multiple Copy Simultaneous Search (MCSS) and Solvation Energy for Exhaustive Docking (SEED) programs. The configurations resulting from the MCSS search were evaluated with a scoring function developed to estimate the binding free energy. SEED calculations were performed using various values for the dielectric constant of the solute. It is found that scores emphasizing non-polar interactions gave a preferential binding site in agreement with that inferred from recent fluorescence and NMR NOESY experiments. The calculated binding affinity of -1.4 to -3.5 kcal/mol is within the measured range of -2.0 +/- 0.5 kcal/mol. The validity of the binding site is suggested by the dynamical stability of the bound glucose when examined with MD simulations with explicit solvent. Alternative binding sites were found in the simulations and their relative stabilities were estimated. The motions of the bound glucose during molecular dynamics simulations are correlated with the motions of the insulin side chains that are in contact with it and with larger scale insulin motions. These results raise the question of whether glucose binding to insulin could play a role in its activity. The results establish the complementarity of molecular dynamics simulations and normal mode analyses with the search for binding sites proposed with small molecule docking programs.

Keywords
Binding Sites, Computer Simulation, Glucose/chemistry, Glucose/metabolism, Insulin/chemistry, Insulin/metabolism, Models, Molecular, Motion, Software
Pubmed
Web of science
Create date
05/02/2018 16:04
Last modification date
20/08/2019 15:16
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