Temperature-sensitive gating of TRPV1 channel as probed by atomistic simulations of its trans- and juxtamembrane domains

Anton O. Chugunov,Pavel E. Volynsky,Roman G. Efremov,Dmitry E. Nolde,Nikolay A. Krylov

doi:10.1038/srep33112

Abstract

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.

Highlights

Ligand — capsaicin — binding to this domain)
In [14] the focus was put on conductance for Ca2+, Na+, K+ ions, and the channel was represented by the pore domain embedded into palmitoyloleoylphosphatidylcholine (POPC) bilayer
To shed some extra light on the molecular aspects of the thermo-sensitive gating and to complement the previously published modeling data, here we compared in great detail open and closed states of TRPV1 channel pore and mapped hydrophobic properties of the pore inner surface, going far beyond initial assessment that was provided by the authors of these structures[7,8]

Summary

Introduction

In the recent work by Poblete et al.,[16] the whole TRPV1 immersed into POPC membrane was simulated with and without bound ligands – phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) and capsaicin The role of the latter ones in channel opening was investigated, especially in the lower gate vicinity. Recently a ligand-binding domain (S1–S4) of TRPV1 was simulated in a lipid bilayer along with capsaicin molecule to discover the role of membrane in binding site access by capsaicin[27] Despite these simulation efforts, the detailed spontaneous dynamics of the gating still remains elusive – just because the aforementioned studies were focused on other molecular aspects of the channel functioning (ion transport, role of ligands, effects of large-scale collective motions, and so on). Based on the accumulated exhaustive set of MD data (in total, c.a. 10 μs), we suggest an original mechanistic model of the temperature-dependent channel gating

Methods

Results

Discussion

Conclusion