Issue 18, 2023

Dissecting the species-specific recognition of Neoseptin 3 by TLR4/MD2 via molecular dynamics simulations

Abstract

Toll-like receptor 4 (TLR4) is crucial in the innate immune response with species-specific recognition. As a novel small-molecule agonist for mouse TLR4/MD2, Neoseptin 3 fails to activate human TLR4/MD2, while the underlying mechanism is unclear. Herein, molecular dynamics simulations were performed to investigate the species-specific molecular recognition of Neoseptin 3. Lipid A, a classic TLR4 agonist showing no apparent species-specific sensing by TLR4/MD2, was also investigated for comparison. Neoseptin 3 and lipid A showed similar binding patterns with mouse TLR4/MD2. Although the binding free energies of Neoseptin 3 interacting with TLR4/MD2 from mouse and human species were similar, protein–ligand interactions and the details of the dimerization interface were substantially different between Neoseptin 3-bound mouse and human heterotetramers at the atomic level. Neoseptin 3 binding made human (TLR4/MD2)2 more flexible than human (TLR4/MD2/Lipid A)2, especially at the TLR4 C-terminus and MD2, which drives human (TLR4/MD2)2 fluctuating away from the active conformation. In contrast to mouse (TLR4/MD2/2*Neoseptin 3)2 and mouse/human (TLR4/MD2/Lipid A)2 systems, Neoseptin 3 binding to human TLR4/MD2 led to the separating trend of the C-terminus of TLR4. Furthermore, the protein–protein interactions at the dimerization interface between TLR4 and the neighboring MD2 in the human (TLR4/MD2/2*Neoseptin 3)2 system were much weaker than those of the lipid A-bound human TLR4/MD2 heterotetramer. These results explained the inability of Neoseptin 3 to activate human TLR4 signaling and accounted for the species-specific activation of TLR4/MD2, which provides insight for transforming Neoseptin 3 as a human TLR4 agonist.

Graphical abstract: Dissecting the species-specific recognition of Neoseptin 3 by TLR4/MD2 via molecular dynamics simulations

Supplementary files

Article information

Article type
Paper
Submitted
01 Mar 2023
Accepted
20 Apr 2023
First published
21 Apr 2023

Phys. Chem. Chem. Phys., 2023,25, 13012-13018

Dissecting the species-specific recognition of Neoseptin 3 by TLR4/MD2 via molecular dynamics simulations

S. Wu, C. Zhang, Y. Wang, P. Li, X. Du and X. Wang, Phys. Chem. Chem. Phys., 2023, 25, 13012 DOI: 10.1039/D3CP00949A

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