Mlok1 Ligand Binding Simulations: Induced Fit Versus Conformational Selection

Many ion channels such as the MloK1 channel are steered by ligand binding via conformational changes. Mainly two binding mechanisms have been proposed, induced fit and conformational selection. Using molecular dynamics simulations, we studied the ligand binding mechanism of cyclic adeonise monophosphate at the cyclic nucleotide binding domain of the MloK1 ion channel of Mesorizobium loti. For this binding domain, crystal structures are available for both the ligand free as well as for the ligand bound conformation, rendering the system an ideal prototype for studying the binding process by atomistic simulations. In the simulations, spontaneous binding was observed. Furthermore, reaction coordinates for the ligand binding as well as for the associated conformational change of the protein were determined. Together with potentials of mean force along these coordinates calculated by umbrella sampling, the results show a relatively fast ligand binding kinetics and a larger free energy barrier for the subsequent conformational change. Calculated free energy differences between both protein conformations during the absence of a ligand allow to distinguish between conformational selection and induced fit.