TY - JOUR
T1 - Dissecting the innate immune recognition of morphine and its metabolites by TLR4/MD2
T2 - an in silico simulation study
AU - Zhang, Xiaozheng
AU - Li, Ran
AU - Xu, Haoran
AU - Wu, Guicai
AU - Wu, Siru
AU - Wang, Hongshuang
AU - Wang, Yibo
AU - Wang, Xiaohui
N1 - Publisher Copyright:
© 2023 The Royal Society of Chemistry.
PY - 2023/10/5
Y1 - 2023/10/5
N2 - A toll-like receptor 4/myeloid differentiation factor 2 complex (TLR4/MD2) has been identified as a non-classical opioid receptor capable of recognizing morphine isomers and activating microglia in a non-enantioselective manner. Additionally, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the major metabolites of morphine, possess similar chemical structures but exhibit distinct effects on TLR4 signaling. However, the specific mechanisms by which morphine isomers and morphine metabolites are recognized by the innate immune receptor TLR4/MD2 are not well understood. Herein, molecular dynamics simulations were performed to dissect the molecular recognition of TLR4/MD2 with morphine isomers, M3G and M6G. Morphine and its (+)-enantiomer, dextro-morphine ((+)-morphine), were found to have comparable binding free energies as well as similar interaction modes when interacting with (TLR4/MD2)2. Binding with morphine and (+)-morphine caused the motion of the F126 loop towards the inside of the MD2 cavity, which stabilizes (TLR4/MD2)2 with similar dimerization interfaces. The binding free energies of M3G and M6G with (TLR4/MD2)2, while lower than those of morphine isomers, were comparable to each other. However, the binding behaviors of M3G and M6G exhibited contrasting patterns when interacting with (TLR4/MD2)2. The glucuronide group of M3G bound to the gating loop of MD2 and formed strong interactions with TLR4*, which stabilizes the active heterotetrameric complex. In contrast, M6G was situated in cavity A of MD2, where the critical interactions between M6G and the residues of TLR4* were lost, resulting in fluctuation of (TLR4/MD2)2 away from the active conformation. These results indicate that the pivotal interactions at the dimerization interface between MD2 and TLR4* in M6G-bound (TLR4/MD2)2 were considerably weaker than those in M3G-bound (TLR4/MD2)2, which partially explains why M6G fails to activate TLR4 signaling. The discoveries from this study will offer valuable insights for the advancement of next-generation TLR4 small molecule modulators based on opioids.
AB - A toll-like receptor 4/myeloid differentiation factor 2 complex (TLR4/MD2) has been identified as a non-classical opioid receptor capable of recognizing morphine isomers and activating microglia in a non-enantioselective manner. Additionally, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the major metabolites of morphine, possess similar chemical structures but exhibit distinct effects on TLR4 signaling. However, the specific mechanisms by which morphine isomers and morphine metabolites are recognized by the innate immune receptor TLR4/MD2 are not well understood. Herein, molecular dynamics simulations were performed to dissect the molecular recognition of TLR4/MD2 with morphine isomers, M3G and M6G. Morphine and its (+)-enantiomer, dextro-morphine ((+)-morphine), were found to have comparable binding free energies as well as similar interaction modes when interacting with (TLR4/MD2)2. Binding with morphine and (+)-morphine caused the motion of the F126 loop towards the inside of the MD2 cavity, which stabilizes (TLR4/MD2)2 with similar dimerization interfaces. The binding free energies of M3G and M6G with (TLR4/MD2)2, while lower than those of morphine isomers, were comparable to each other. However, the binding behaviors of M3G and M6G exhibited contrasting patterns when interacting with (TLR4/MD2)2. The glucuronide group of M3G bound to the gating loop of MD2 and formed strong interactions with TLR4*, which stabilizes the active heterotetrameric complex. In contrast, M6G was situated in cavity A of MD2, where the critical interactions between M6G and the residues of TLR4* were lost, resulting in fluctuation of (TLR4/MD2)2 away from the active conformation. These results indicate that the pivotal interactions at the dimerization interface between MD2 and TLR4* in M6G-bound (TLR4/MD2)2 were considerably weaker than those in M3G-bound (TLR4/MD2)2, which partially explains why M6G fails to activate TLR4 signaling. The discoveries from this study will offer valuable insights for the advancement of next-generation TLR4 small molecule modulators based on opioids.
UR - https://www.scopus.com/pages/publications/85175569314
U2 - 10.1039/d3cp03715k
DO - 10.1039/d3cp03715k
M3 - Article
C2 - 37882236
AN - SCOPUS:85175569314
SN - 1463-9076
VL - 25
SP - 29656
EP - 29663
JO - Physical Chemistry Chemical Physics
JF - Physical Chemistry Chemical Physics
IS - 43
ER -