Exploring the activation mechanism of TRPM8 channel by targeted MD simulations.

The TRPM8 cation channel belongs to the superfamily of transient receptor potential (TRP) channels. It is involved in non-painful cool sensation and triggered by diverse chemical and physical stimuli whose precise activation mechanism is still unknown. The study presents a set of targeted molecular dynamics (MD) simulations involving selected complexes of the TRPM8 channel whose homology model was recently generated by some of us. More in detail, the MD simulations concerned the TRPM8 alone and in complex with agonists and antagonists. These simulations were focused on voltage sensor module and designed to validate the ligand induced activation mechanism as hypothesized in our previous study. The obtained results are in encouraging agreement with the proposed mechanism and allow a clear discrimination between agonists and antagonists. In addition, the MD runs confirm that the agonist binding triggers a set of concatenate conformational shifts which induce the approaching of the S3 segment toward the S4 segment and culminate in an extension of the latter. By introducing suitable constraints, the reported MD simulations were rendered as fast as possible in order to achieve a truly productive compromise between reliability and computational costs. The obtained results emphasize that suitably targeted MD runs can be fast enough to be systematically applied to predict the bioactivity of large datasets providing it as an useful tool in rational ligand design process.