TY - JOUR

T1 - In-silico study of the interactions between acylated glucagon like-peptide-1 analogues and the native receptor

AU - Frimann, Tine Maja

AU - Ko, Suk Kyu

AU - Harris, Pernille

AU - Bukrinski, Jens Thostrup

AU - Peters, Günther H.J.

N1 - Publisher Copyright: © 2022 Informa UK Limited, trading as Taylor & Francis Group.

PY - 2023

Y1 - 2023

N2 - We have performed a series of multiple molecular dynamics (MD) simulations of glucagon-like peptide-1 (GLP-1) and acylated GLP-1 analogues in complex with the endogenous receptor (GLP-1R) to obtain a molecular understanding of how fatty acid (FA) chain structure, acylation position on the peptide, and presence of a linker affect the binding. MD simulations were analysed to extract heatmaps of receptor–peptide interaction patterns and to determine the free energy of binding using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approach. The extracted free energies from MM-PBSA calculations are in qualitative agreement with experimentally determined potencies. Furthermore, the interaction patterns seen in the receptor–GLP-1 complex simulations resemble previously reported binding interactions validating the simulations. Analysing the receptor–GLP-1 analogue complex simulations, we found that the major differences between the systems stem from FA interactions and positioning of acylation in the peptide. Hydrophobic interactions between the FA chain and a hydrophobic patch on the extracellular domain contribute significantly to the binding affinity. Acylation on Lys26 resulted in noticeably more interactions between the FA chain and the extracellular domain hydrophobic patch than found for acylation on Lys34 and Lys38, respectively. The presence of a charged linker between the peptide and FA chain can potentially stabilise the complex by forming hydrogen bonds to arginine residues in the linker region between the extracellular domain and the transmembrane domain. A molecular understanding of the fatty acid structure and its effect on binding provides important insights into designing acylated agonists for GLP-1R. Communicated by Ramaswamy H. Sarma.

AB - We have performed a series of multiple molecular dynamics (MD) simulations of glucagon-like peptide-1 (GLP-1) and acylated GLP-1 analogues in complex with the endogenous receptor (GLP-1R) to obtain a molecular understanding of how fatty acid (FA) chain structure, acylation position on the peptide, and presence of a linker affect the binding. MD simulations were analysed to extract heatmaps of receptor–peptide interaction patterns and to determine the free energy of binding using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approach. The extracted free energies from MM-PBSA calculations are in qualitative agreement with experimentally determined potencies. Furthermore, the interaction patterns seen in the receptor–GLP-1 complex simulations resemble previously reported binding interactions validating the simulations. Analysing the receptor–GLP-1 analogue complex simulations, we found that the major differences between the systems stem from FA interactions and positioning of acylation in the peptide. Hydrophobic interactions between the FA chain and a hydrophobic patch on the extracellular domain contribute significantly to the binding affinity. Acylation on Lys26 resulted in noticeably more interactions between the FA chain and the extracellular domain hydrophobic patch than found for acylation on Lys34 and Lys38, respectively. The presence of a charged linker between the peptide and FA chain can potentially stabilise the complex by forming hydrogen bonds to arginine residues in the linker region between the extracellular domain and the transmembrane domain. A molecular understanding of the fatty acid structure and its effect on binding provides important insights into designing acylated agonists for GLP-1R. Communicated by Ramaswamy H. Sarma.

KW - Acylated peptides

KW - binding free energy

KW - configurational entropy

KW - MM-PBSA

KW - molecular dynamics simulations

KW - peptide-receptor interactions

U2 - 10.1080/07391102.2022.2078409

DO - 10.1080/07391102.2022.2078409

M3 - Journal article

C2 - 35612899

AN - SCOPUS:85131074791

VL - 41

SP - 5007

EP - 5021

JO - Journal of Biomolecular Structure and Dynamics

JF - Journal of Biomolecular Structure and Dynamics

SN - 0739-1102

IS - 11

ER -