Temperature-sensitive gating of TRPV1 channel as probed by atomistic simulations of its trans- and juxtamembrane domains.
Heat-activated transient receptor potential channel TRPV1 is one of the most studied eukaryotic proteins involved in temperature sensation. Upon heating, it exhibits rapid reversible pore gating, which depolarizes neurons and generates action potentials. Underlying molecular details of such effects in the pore region of TRPV1 is of a crucial importance to control temperature responses of the organism. Despite the spatial structure of the channel in both open (O) and closed (C) states is known, microscopic nature of channel gating and mechanism of thermal sensitivity are still poorly understood. In this work, we used unrestrained atomistic molecular dynamics simulations of TRPV1 (without N- and C-terminal cytoplasmic domains) embedded into explicit lipid bilayer in its O- and C-states. We found that the pore domain with its neighboring loops undergoes large temperature-dependent conformational transitions in an asymmetric way, when fragments of only one monomer move with large amplitude, freeing the pore upon heating. Such an asymmetrical gating looks rather biologically relevant because it is faster and more reliable than traditionally proposed "iris-like" symmetric scheme of channel opening. Analysis of structural, dynamic, and hydrophobic organization of the pore domain revealed entropy growth upon TRPV1 gating, which is in line with current concepts of thermal sensitivity.
M.M. Shemyakin &Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, Moscow 117997, Russia.
Anton O
AO
Chugunov
M.M. Shemyakin &Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, Moscow 117997, Russia.
Pavel E
PE
Volynsky
M.M. Shemyakin &Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, Moscow 117997, Russia.|Joint Supercomputer Center, Russian Academy of Sciences, Leninsky prospect, 32a, Moscow 119991, Russia.
Nikolay A
NA
Krylov
M.M. Shemyakin &Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, Moscow 117997, Russia.|Joint Supercomputer Center, Russian Academy of Sciences, Leninsky prospect, 32a, Moscow 119991, Russia.
Dmitry E
DE
Nolde
M.M. Shemyakin &Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, Moscow 117997, Russia.|National Research University Higher School of Economics, Myasnitskaya ul. 20, 101000 Moscow, Russia.
Roman G
RG
Efremov
D003198:Computer Simulation; D006358:Hot Temperature; D006801:Humans; D056004:Molecular Dynamics Simulation; D000072417:Protein Domains; D050916:TRPV Cation Channels / Q000737:chemistry*
D050916:TRPV Cation Channels; C494482:TRPV1 protein, human