Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

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.

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