Transient receptor potential melastatin 8 (TRPM8) is a member of the TRP channel, a cold-activated non-selective cation channel, and an important target for the treatment of asthma, migraine and other diseases. TRPM8 is activated by chemical ligands such as menthol and icilin, and physical stimulus such as temperature and voltage. TRPM8 channel regulation is accomplished by a conformational change that allows the protein to switch between two alternative (closed vs. open) conformations, a process known as gating. Activated-TRPM8 channel is permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. There have been various studies aiming to understand the molecular mechanism of TRPM8 channel gating, such as functional studies, mutagenesis data and crystallographic data. However, the detailed gating mechanism of TRPM8 remains obscure.
Here, we constructed two 3-dimentional structures of TRPM8 channels using the SWISS-MODEL server. The data show that there are a few of gates that formed by some amino acids along the central pore of channel.  The flexibility of the amino acids is great during dynamics simulation process, because the linker between helix S6 and TRP helix is in loop state, which compose the inner helix gate. There is only one gate when the linker is in helix state. During the inner helix changed from loop to helix, the new interactions are formed between the key and surrounding amino acids, which can stabilize the helix state. The allosteric conformation of the amino acids along the pore will change from order states to disorder. The results of the SMD simulation demonstrate that the conformational change of the inner helix gate is interconnected with allosteric site of the selectivity filter. The inner helix in a loop state increases the barrier of the selective filter, which blocks the ion permeation through the pore. So the inner gating helix changes conformation from a loop to a helix, which is the first step toward channel pore opening.
 

TRPM8 channel,molecular dynamics simulation,gating mechanism,allosteric conformation