A Crucial Role for Side-Chain Conformation in the Versatile Charge Selectivity of Cys-Loop Receptors.

Whether synaptic transmission is excitatory or inhibitory depends, to a large extent, on whether the ion channels that open upon binding the released neurotransmitter conduct cations or anions. The mechanistic basis of the opposite charge selectivities of Cys-loop receptors has only recently begun to emerge. It is now clear that ionized side chains-whether pore-facing or buried-in the first α-helical turn of the second transmembrane segments underlie this phenomenon and that the electrostatics of backbone atoms are not critically involved. Moreover, on the basis of electrophysiological observations, it has recently been suggested that not only the sign of charged side chains but also their conformation are crucial determinants of cation-anion selectivity. To challenge these ideas with the chemical and structural rigor that electrophysiological observations naturally lack, we performed molecular dynamics, Brownian dynamics, and electrostatics calculations of ion permeation. To this end, we used structural models of the open-channel conformation of the α1 glutamate-gated Cl