engleski

A molecular dynamics workflow for interrogating PUFA derived lipid mediator interactions with the TRPV1 channel

Various fatty acyl lipid mediators derived from dietary polyunsaturated fatty acids (PUFAs) modulate nociception. Many of these lipid mediators can directly bind ion channels located on sensory nerves, including the transient receptor potential vanilloid 1 (TRPV1) channel. Linoleic acid, the most abundant PUFA in the modern diet, is a precursor of many pronociceptive lipid mediators with potential for TRPV1 binding, and excessive dietary linoleic acid intake is associated with exaggerated nociceptive hypersensitivity. Although recommendations about dietary fatty acid intake exist for some diseases (e.g., cardiovascular disease), the role of dietary fatty acids in promoting pain disorders is not completely understood. Molecular dynamic simulation offers a powerful strategy for interrogating lipid mediator-TRPV1 interactions. All-atom simulations of the TRPV1 channel were prepared using CHARMM-GUI Membrane Builder and OPMprotocols were used to position and orient the channel in a membrane bilayer. The composition in the membrane bilayer in this all-atom system is as follows: 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl- phosphatidylethanolamine (POPE), 1- palmitoyl-2-oleoyl-phosphatidic acid (POPA), 1- palmitoyl-2-oleoyl-phosphatidylserine (POPS), N-palmitoyl-sphingomyelin (PSM), 1- palmitoyl-2-oleoyl-phosphatidylinositol (POPI), cholesterol (CHOL). Multi-scale molecular dynamics simulations were used to identify amino acid residues that are most affected by lipid mediator binding in each of the four subunits. Each step in the peristaltic motion was described down to the individual atoms using all-atom approaches and statistical analysis of the correlated motion between sub-units. Each molecular dynamic simulation of lipid mediator-bound TRPV1 structures was compared to the TRPV1 structure with no bound agonist and to the capsaicin-bound TRPV1 structure. Taken together, this molecular dynamic workflow can help elucidate molecular mechanism underlying modulation of nociception by fatty acyl lipid mediators.

Molecular dynamics ; PUFA lipid mediators ; TRPV1 channel

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