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

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 - https://www.scopus.com/pages/publications/85195255543

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 -