Molecular basis for voltage sensitivity in membrane proteins

ABSTRACT Voltage-sensitive membrane proteins are united by the ability to transform changes in the membrane potential into mechanical work. They are responsible for a spectrum of key physiological processes in living organisms, including electric signaling and progression along the cell cycle. While the voltage-sensing mechanism has been well characterized for some membrane proteins such as voltage-gated ion channels, for others even the location of the voltage-sensing elements remains unknown. The detection of these elements using experimental techniques is complicated due to the large diversity of membrane proteins. Here, we suggest a computational approach to predict voltage-sensing elements in any membrane protein independent of structure or function. It relies on the estimation of the capacity of a protein to respond to changes in the membrane potential. We first show how this property correlates well with voltage sensitivity by applying our approach to a set of membrane proteins including voltage-sensitive and voltage-insensitive ones. We further show that it correctly identifies true voltage-sensitive residues in the voltage sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions potentially involved in the response to voltage. The suggested approach is fast and simple and allows for characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application prior to mutagenesis experiments will allow for significant reduction of the number of potential voltage-sensitive elements to be tested.