Energy Landscapes and Structural Ensembles of Glucagon-like Peptide-1 Monomers.

ABSTRACT: While GLP-1 and its analogues are important pharmaceutical agents in the treatment of type 2 diabetes and obesity, their susceptibility to aggregate into amyloid fibrils poses a significant safety issue. Many factors may contribute to the aggregation propensity, including pH. While it is known that the monomeric structure of GLP-1 has a strong impact on primary nucleation, probing its diverse structural ensemble is challenging. Here, we investigated the monomer structural ensembles at pH 3, 4, and 7.5 using state-of-the-art computational methods in combination with experimental data. We found significant stabilization of β-strand structures and destabilization of helical structures at lower pH, correlating with observed aggregation lag times, which are lower under these conditions. We furt

SUBMITTER: Keith AD 

PROVIDER: S-EPMC11182347 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature