Comment on "On the Functional Annotation of Open-Channel Structures in the Glycine Receptor"

Recently, we reported the simulation of a stable open state of the glycine receptor. Central to the stability of the simulations was the behavior of the highly conserved leucine residues at the 9' gate, which were found to rotate into adjacent pockets, thus providing a structural rationale for decades of biochemical observations. In contrast, a previously reported model from Cerdan et al. (2018) resembled a more collapsed state. However, in support of their model, they draw attention to the agreement between calculated and experimental conductance measurements and argue that our model tends to overestimate ion flow. Here, we argue that there are many pitfalls with this approach and that the apparent agreement most likely reflects a fortuitous cancellation of errors. The computed values are highly sensitive to very small changes in model parameters. It is also likely that polarization effects will be very significant, and these have not yet been considered.