Voltar
Artigo Acesso aberto Produção Nacional Revisado por pares
BIBTEX RIS

TLR4 Recruitment into Lipid Rafts Studied by Coarse Grained MD Simulation

2018; Elsevier BV; Volume: 114; Issue: 3 Linguagem: Inglês

10.1016/j.bpj.2017.11.440

ISSN

1542-0086

Autores

Paulo C. T. Souza, Tsjerk A. Wassenaar, Munir S. Skaf, ‪Siewert J. Marrink,

Tópico(s)

Water Systems and Optimization

Resumo

Toll-like receptors 4 (TLR4) are transmembrane proteins of the innate immune system responsible for recognizing lipopolysaccharides (LPS), essential components of the Gram-negative bacteria outer membrane. The association of LPS to TLR4 promotes its migration to cell membrane rafts and its homodimerization, which triggers an inflammatory response. Given its role in the innate immune system, TLR4 is an important target in drug development, especially for the treatment of infections and acute inflammations such as sepsis. In the last years, in vitro and in vivo experiments demonstrated that dietary saturated fatty acids (SFAs) can also activate TLR4, linking obesity and inflammation. Conversely, polyunsaturated fatty acids (PUFAs) have showed anti-inflammatory properties and can inhibit TLR4 activation by LPS. The molecular reasons underlying TLR4 trafficking between the membrane microdomains and also the agonist/antagonist action of SFAs and PUFAs are largely unknown. In this study, we applied MARTINI coarse grained molecular dynamics (MD) simulations to study the influence of SFAs, PUFAs and LPS on the TLR4 partitioning between liquid-order (Lo) and liquid-disorder (Ld) phases of a raft membrane model. In agreement with existing experimental data, our simulations indicate that LPS and fatty acids influence the partitioning of the TLR4 transmembrane domain: SFAs and LPS induce the recruitment into the Lo phase while PUFAs keep the protein in the Ld phase. Our results provide insights into the driving forces underlying this sorting mechanism. Furthermore, our simulations reveal that TLR4 phase location affects its orientation in the membrane with a direct impact on the possible dimerization binding modes.

Referência(s)