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Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Session IV Abstracts
Self-assembly of a Glucagon-like Peptide 1 Analogue: Bridging Experiment and
Simulations
Günther H. Peters
1
, Maria N. Elf-Lind
1
, Pernille Sønderby
1
, Jens T. Bukrinski
2
, Pernille
Harris
1
.
1
Technical University of Denmark, Kgs. Lyngby, Denmark,
2
Novozymes A/S, Bagsværd,
Denmark.
In the present study, we have studied the self-assembly of the glucagon-like peptide 1 (GLP-1)
analogue, liraglutide, which is an agonist and is used in the treatment of type 2 Diabetes
Mellitus. Compared to GLP-1, liraglutide has an added fatty acid moiety and a gamma-glutamic
acid linker on lysine-26, and a lysine to arginine substitution at residue 34. The modification on
lysine-26 causes concentration-independent heptamerisation of liraglutide as suggested by small-
angle X-ray scattering (SAXS) data. Using the SAXS data as input for
ab initio
shape
determination suggested global shape of the heptamer. The orientation of the fatty acid chains
could, however, not be deduced. To bridge the global shape information to an atomistic
description of the heptamer, full-atomic and coarse grained molecular dynamics simulations are
applied. A reverse transformation from coarse grained to atomistic description allows to access a
large time scale in the simulations and at the same time to study the intermolecular interactions
on the molecular level as well as the dynamics and stability of the complexes. Different start
conformations of heptamers are generated and simulated. To validate the simulated complexes,
theoretical SAXS curved are calculated and compared with the experimental SAXS profiles.
