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Methamphetamine (METH) is one of the highly addictive non-opioid psychostimulants, acting as a xenobiotic-associated molecular pattern to target TLR4 and activate microglia. However, the molecule recognition of METH by innate immune receptor TLR4/MD-2 is not well understood. METH exists in two enantiomeric forms and it is unclear whether the TLR4 innate immune recognition with METH is stereoselective. Herein molecular dynamics simulations were performed to dissect the recognition of (+)-METH and (-)-METH by TLR4/MD-2 at the atomic level. Amphetamine (AMPH), which is an analog of METH, was also investigated for comparison. Computational simulations indicate METH binds into the interaction interface between MD-2 as well as TLR4* that is from the adjacent copy of TLR4-MD-2, therefore stabilizing the active heterotetramer (TLR4/MD-2)2 complex. The calculated binding free energies and potential of mean force values show (-)-METH and (+)-METH have similar TLR4/MD-2 binding affinity. Further dynamics analyses of bindings with TLR4/MD-2 indicate that (-)-METH and (+)-METH behave similarly. Unlike the stereo-selective neuron stimulating activities of METH, no enantioselectivity was observed for METH interacting with TLR4/MD-2 complex as well as activating TLR4 signaling. Compared to METH, AMPH showed much weaker interactions with TLR4/MD-2, indicating that the substituted methyl group is critical in the molecular recognition of METH by TLR4/MD-2. In all, this study provides a molecular insight into the innate immune recognition of METH, which demonstrates that METH could be non-enantioselectively sensed by TLR4/MD-2.
This article was published in the following journal.
Name: Journal of chemical information and modeling
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A pattern recognition receptor that forms heterodimers with TOLL-LIKE RECEPTOR 2.
A pattern recognition receptor that forms heterodimers with other TOLL-LIKE RECEPTORS. It interacts with multiple ligands including PEPTIDOGLYCAN, bacterial LIPOPROTEINS, lipoarabinomannan, and a variety of PORINS.
A family of pattern recognition receptors characterized by an extracellular leucine-rich domain and a cytoplasmic domain that share homology with the INTERLEUKIN 1 RECEPTOR and the DROSOPHILA toll protein. Following pathogen recognition, toll-like receptors recruit and activate a variety of SIGNAL TRANSDUCING ADAPTOR PROTEINS.
A cytoplasmic receptor and peroxin that contains a series of TETRACOTIPEPTIDE REPEATS and binds to PEROXISOME TARGETING SIGNAL 1 (SKL-type). It is essential for protein import into PEROXISOMES; mutations in the PEX5 gene are associated with PEROXISOMAL DISORDERS such as ZELLWEGER SYNDROME.
An intracellular signaling adaptor protein that plays a role in TOLL-LIKE RECEPTOR and INTERLEUKIN 1 RECEPTORS signal transduction. It forms a signaling complex with the activated cell surface receptors and members of the IRAK KINASES.