Investigations of Albumin-Insulin Detemir Complexes Using Molecular Dynamics Simulations and Free Energy Calculations
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Investigations of Albumin-Insulin Detemir Complexes Using Molecular Dynamics Simulations and Free Energy Calculations. / Ryberg, Line A.; Sønderby, Pernille; Bukrinski, Jens T.; Harris, Pernille; Peters, Günther H.J.
In: Molecular Pharmaceutics, Vol. 17, No. 1, 06.01.2020, p. 132-144.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Investigations of Albumin-Insulin Detemir Complexes Using Molecular Dynamics Simulations and Free Energy Calculations
AU - Ryberg, Line A.
AU - Sønderby, Pernille
AU - Bukrinski, Jens T.
AU - Harris, Pernille
AU - Peters, Günther H.J.
PY - 2020/1/6
Y1 - 2020/1/6
N2 - Insulin detemir is a lipidated insulin analogue that obtains a half-life extension by oligomerization and reversible binding to human serum albumin. In the present study, the complex between a detemir hexamer and albumin is investigated by an integrative approach combining molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations, and dynamic light scattering (DLS) experiments. Recent reported small-angle X-ray scattering data could not unambiguously resolve the exact binding site of detemir on albumin. We therefore applied MD simulations to deduce the binding site and key protein-protein interactions. MD simulations were started from initial complex structures based on the SAXS models, and free energies of binding were estimated from the simulations by using the MM-PBSA approach for the different binding positions. The results suggest that the overlapping FA3-FA4 binding site (named FA4) is the most favorable site with a calculated free energy of binding of -28 ± 6 kcal/mol and a good fit to the reported SAXS data throughout the simulations. Multiple salt bridges, hydrogen bonds, and favorable van der Waals interactions are observed in the binding interface that promote complexation. The binding to FA4 is further supported by DLS competition experiments with the prototypical FA4 ligand, ibuprofen, showing displacement of detemir by ibuprofen. This study provides information on albumin-detemir binding on a molecular level, which could be utilized in a rational design of future lipidated albumin-binding peptides.
AB - Insulin detemir is a lipidated insulin analogue that obtains a half-life extension by oligomerization and reversible binding to human serum albumin. In the present study, the complex between a detemir hexamer and albumin is investigated by an integrative approach combining molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations, and dynamic light scattering (DLS) experiments. Recent reported small-angle X-ray scattering data could not unambiguously resolve the exact binding site of detemir on albumin. We therefore applied MD simulations to deduce the binding site and key protein-protein interactions. MD simulations were started from initial complex structures based on the SAXS models, and free energies of binding were estimated from the simulations by using the MM-PBSA approach for the different binding positions. The results suggest that the overlapping FA3-FA4 binding site (named FA4) is the most favorable site with a calculated free energy of binding of -28 ± 6 kcal/mol and a good fit to the reported SAXS data throughout the simulations. Multiple salt bridges, hydrogen bonds, and favorable van der Waals interactions are observed in the binding interface that promote complexation. The binding to FA4 is further supported by DLS competition experiments with the prototypical FA4 ligand, ibuprofen, showing displacement of detemir by ibuprofen. This study provides information on albumin-detemir binding on a molecular level, which could be utilized in a rational design of future lipidated albumin-binding peptides.
KW - dynamic light scattering
KW - free energy calculations
KW - human serum albumin
KW - insulin detemir
KW - molecular dynamics simulations
KW - protein-protein complexes
KW - small-angle X-ray scattering
U2 - 10.1021/acs.molpharmaceut.9b00839
DO - 10.1021/acs.molpharmaceut.9b00839
M3 - Journal article
C2 - 31790268
AN - SCOPUS:85077134761
VL - 17
SP - 132
EP - 144
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 1
ER -
ID: 249865140