Dear Editors,

The crystal structure of cASIC1 provides a framework for probing the mechanism underlying the gating of ASICs. Recently, based on the crystal structure of cASIC1, we performed a study on the dynamics-function relationship for this channel using molecular simulation, mutagenesis and electrophysiological methods 3. The results demonstrated that the current X-ray crystal structure of cASIC1 is a reasonable conformation that is biologically relevant and should be a good starting structure for both computational simulations and experimental studies. However, concerns regarding the validity of the crystal structure of ASIC1 still exist. One concern is why the entire architecture composed of three identical subunits is asymmetric, especially that of the TM domain (Figure 1A). Shaikh and Tajkhorshid 4 argued that this asymmetry of ASIC1 structure may be an artifact induced by crystal packing. Another concern is that the current crystal structure of cASIC1 reflects the desensitized/closed, state, which may hinder further insights into the behaviors of the channel. To clarify these concerns and to test the existence of other biologically relevant conformations of ASIC1, we performed a conformational sampling analysis on this channel on the basis of its crystal structure.

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