Predicting conduction properties of TMC proteins involved in sensory perception in silico

The poorly characterized family of transmembrane channel-like (TMC) proteins, consisting of eight members in mammals, is loosely related to the TMEM16 family of membrane proteins that can function as lipid scramblases as well as cation or anion channels. Two TMC proteins, TMC1 and TMC2, are expected to be cation channels mediating inner ear mechanotransduction, whereas TMC4 has been recently proposed to function as an anion channel involved in taste perception. In addition, TMC1 might mediate lipid scrambling. While several experimental studies have been carried out to back these claims, an atomistic picture of conduction mechanisms and possible scramblase activity is still missing. Here we use AlphaFold2 models of TMCs along with equilibrium and non-equilibrium all-atom molecular dynamics simulations to predict conduction properties and function of various family members. Simulations show robust cation conduction for TMC1 and TMC2, while TMC4 is predicted to conduct anions. These TMC simulations are shedding light on ion-conduction pathways and important residues for ion-conduction and selectivity while suggesting mechanisms of activation across this family of membrane proteins.