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Heat activation mechanism of TRPV1: New insights from molecular dynamics simulation.

ABSTRACT: As a member of the transient receptor potential (TRP) channels superfamily, the TRPV1 channel undergoes a closed-to-open gating transition in response to various physical and chemical stimuli including heat. Thanks to recent progress in cryo-electron microscopy, high-resolution structures are becoming available for various TRP channels including TRPV1. This has enabled us to study the molecular mechanism of TRPV1 channel gating by using molecular simulation. Here we review recent progress in molecular simulations of TRPV1 channel by us and others, with focus on our molecular dynamics (MD) simulations of TRPV1 at different temperatures. While no consensus has been reached on the heat activation mechanism of TRPV1, the simulations have offered specific predictions and models for future experimental studies to test.

SUBMITTER: Zheng W

PROVIDER: S-EPMC6601542 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Heat activation mechanism of TRPV1: New insights from molecular dynamics simulation.

Zheng Wenjun W Wen Han H

Temperature (Austin, Tex.) 20190219 2

As a member of the transient receptor potential (TRP) channels superfamily, the TRPV1 channel undergoes a closed-to-open gating transition in response to various physical and chemical stimuli including heat. Thanks to recent progress in cryo-electron microscopy, high-resolution structures are becoming available for various TRP channels including TRPV1. This has enabled us to study the molecular mechanism of TRPV1 channel gating by using molecular simulation. Here we review recent progress in mol ...[more]

PMID: 31286023

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Project description:As a key cellular sensor, the TRPV1 cation channel undergoes a gating transition from a closed state to an open state in response to various physical and chemical stimuli including noxious heat. Despite years of study, the heat activation mechanism of TRPV1 gating remains enigmatic at the molecular level. Toward elucidating the structural and energetic basis of TRPV1 gating, we have performed molecular dynamics (MD) simulations (with cumulative simulation time of 3 μs), starting from the high-resolution closed and open structures of TRPV1 solved by cryo-electron microscopy. In the closed-state simulations at 30°C, we observed a stably closed channel constricted at the lower gate (near residue I679), while the upper gate (near residues G643 and M644) is dynamic and undergoes flickery opening/closing. In the open-state simulations at 60°C, we found higher conformational variation consistent with a large entropy increase required for the heat activation, and both the lower and upper gates are dynamic with transient opening/closing. Through ensemble-based structural analyses of the closed state versus the open state, we revealed pronounced closed-to-open conformational changes involving the membrane proximal domain (MPD) linker, the outer pore, and the TRP helix, which are accompanied by breaking/forming of a network of closed/open-state specific hydrogen bonds. By comparing the closed-state simulations at 30°C and 60°C, we observed heat-activated conformational changes in the MPD linker, the outer pore, and the TRP helix that resemble the closed-to-open conformational changes, along with partial formation of the open-state specific hydrogen bonds. Some of the residues involved in the above key hydrogen bonds were validated by previous mutational studies. Taken together, our MD simulations have offered rich structural and dynamic details beyond the static structures of TRPV1, and promising targets for future mutagenesis and functional studies of the TRPV1 channel. Proteins 2016; 84:1938-1949. © 2016 Wiley Periodicals, Inc.

Project description: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.

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Heat activation mechanism of TRPV1: New insights from molecular dynamics simulation.

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Heat activation mechanism of TRPV1: New insights from molecular dynamics simulation.

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