Abstract
Transient receptor potential vanilloid subtype 1 (TRPV1) is a heat-sensitive ion channel also involved in pain sensation, and is the receptor for capsaicin, the active ingredient of hot chili peppers. The recent structures of TRPV1 revealed putative ligand density within the S1 to S4 voltage-sensor-like domain of the protein. However, questions remain regarding the dynamic role of the lipid bilayer in ligand binding to TRPV1. Molecular dynamics simulations were used to explore behavior of capsaicin in a 1-palmitoyl-2-oleoyl phosphatidylcholine bilayer and with the target S1–S4 transmembrane helices of TRPV1. Equilibrium simulations reveal a preferred interfacial localization for capsaicin. We also observed a capsaicin molecule flipping from the extracellular to the intracellular leaflet, and subsequently able to access the intracellular TRPV1 binding site. Calculation of the potential of mean force (i.e., free energy profile) of capsaicin along the bilayer normal confirms that it prefers an interfacial localization. The free energy profile indicates that there is a nontrivial but surmountable barrier to the flipping of capsaicin between opposing leaflets of the bilayer. Molecular dynamics of the S1–S4 transmembrane helices of the TRPV1 in a lipid bilayer confirm that Y511, known to be crucial to capsaicin binding, has a distribution along the bilayer normal similar to that of the aromatic group of capsaicin. Simulations were conducted of the TRPV1 S1–S4 transmembrane helices in the presence of capsaicin placed in the aqueous phase, in the lipid, or docked to the protein. No stable interaction between ligand and protein was seen for simulations initiated with capsaicin in the bilayer. However, interactions were seen between TRPV1 and capsaicin starting from the cytosolic aqueous phase, and capsaicin remained stable in the majority of simulations from the docked pose. We discuss the significance of capsaicin flipping from the extracellular to the intracellular leaflet and mechanisms of binding site access by capsaicin.
Highlights
Transient receptor potential (TRP) channels are a diverse set of nonselective cation channels found in eukaryotic cells
Our results show the role of the lipid bilayer in capsaicin localization and of flip-flop when considering its binding to transient receptor potential vanilloid subtype 1 (TRPV1)
The capsaicin A region localizes alongside the phospholipid carbonyls, as does the Y511 of TRPV1
Summary
Transient receptor potential (TRP) channels are a diverse set of nonselective cation channels found in eukaryotic cells. These channels are often involved in sensory transduction, participating in the direct detection of stimuli ranging from osmotic sensing to temperature change, and are crucial members of lipid-based signaling pathways [1,2]. Among the diversity of TRP channels are the receptors for molecules such as menthol, camphor, mustard, and capsaicin, the latter being responsible for the pungent hot nature of chili peppers [3]. Along with other members of the TRP channel family, known to play key roles in temperature sensation and other sensory functions [5], TRPV1 is a prominent therapeutic target [6,7]. As capsaicin is a lipophilic molecule (Fig. 1 A) and the TRPV1 channel is an integral membrane protein with an overall transmembrane (TM) architecture resembling that of voltage-gated potas-
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