TY - JOUR
T1 - Energy Landscapes and Structural Ensembles of Glucagon-like Peptide-1 Monomers
AU - Keith, Alasdair D
AU - Brichtová, Eva Přáda
AU - Barber, Jack G
AU - Wales, David J
AU - Jackson, Sophie E
AU - Röder, Konstantin
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society
PY - 2024/6/13
Y1 - 2024/6/13
N2 - 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 further identified helical defects at pH 4, which led to the fastest observed aggregation, in agreement with our far-UV circular dichroism data. The detailed atomistic structures that result from the computational studies help to rationalize the experimental results on the aggregation propensity of GLP-1. This work provides a new insight into the pH-dependence of monomeric structural ensembles of GLP-1 and connects them to experimental observations.
AB - 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 further identified helical defects at pH 4, which led to the fastest observed aggregation, in agreement with our far-UV circular dichroism data. The detailed atomistic structures that result from the computational studies help to rationalize the experimental results on the aggregation propensity of GLP-1. This work provides a new insight into the pH-dependence of monomeric structural ensembles of GLP-1 and connects them to experimental observations.
UR - http://www.scopus.com/inward/record.url?scp=85195255543&partnerID=8YFLogxK
U2 - 10.1021/acs.jpcb.4c01794
DO - 10.1021/acs.jpcb.4c01794
M3 - Article
C2 - 38831581
SN - 1520-6106
VL - 128
SP - 5601
EP - 5611
JO - The journal of physical chemistry. B
JF - The journal of physical chemistry. B
IS - 23
ER -
