Structural properties of short glucagon-like peptide-1 in various solvents investigated by molecular dynamics simulations

Abstract

It has been reported that short glucagon-like peptide-1 (sGLP-1), one of glucagon-like peptide 1 (GLP-1) analogues, has the same effect in treating type 2 diabetes mellitus (T2DM) as GLP-1 with increased half-life in human body. Although the high-resolution structure of complex of GLP-1 and its receptor has been achieved, the relationship between the structure of GLP-1 before recognition and its final function is still not clear. As for sGLP-1, few studies attempt to investigate the influences of different conditions on its structure. In present paper, molecular dynamics simulations were applied to explore molecular details of sGLP-1 under various environments. The results demonstrated that in low pH value solvent, the additional helical residue of Pro6 and the flexible N-terminal cannot keep [Formula: see text] helix biological conformation. At pH 3, the structure has undergone significant changes, resulting in the shortest helical length. Further studies showed that protonation states of Glu21 mainly determined the secondary structure of sGLP-1 when pH values increased from 3 to 7. Interestingly, with ions concentration varying from 0.18% to 0.72%, the fluctuating trend of backbone RMSDs is consistent with that of [Formula: see text] helix structure of sGLP-1. The structure of sGLP-1 had less helix content and became more flexible when temperatures increased in the range from 305[Formula: see text]K to 320[Formula: see text]K. Meanwhile, in mixtures of water and 2,2,2-trifluoroethanol (TFE) sGLP-1 showed a rigid structure with an additional helical residue (Pro6) at the N-terminal of original helix content.