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Proteins. 2016 Dec;84(12):1938-1949. doi: 10.1002/prot.25177. Epub 2016 Oct 24.

Toward elucidating the heat activation mechanism of the TRPV1 channel gating by molecular dynamics simulation.

Author information

1
Department of Physics, State University of New York at Buffalo, Buffalo, New York, 14260.
2
Department of Physiology and Biophysical Sciences, State University of New York at Buffalo, Buffalo, New York, 14260.

Abstract

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.

KEYWORDS:

TRPV1 channel; average structure; gating; heat activation; hydrogen bonds; membrane proximal domain; molecular dynamics; principal component analysis; root mean square fluctuation

PMID:
27699868
PMCID:
PMC5118185
DOI:
10.1002/prot.25177
[Indexed for MEDLINE]
Free PMC Article

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