Molecular Determinants of Voltage Sensor Domain Activation

Abstract

The voltage sensor domain (VSD) is a four transmembrane segments protein domain that confers voltage sensitivity to ion channels and other proteins. The VSD senses changes in the external potential through its highly positively charged fourth transmembrane segment (S4). The activation mechanism involves a complex, helical screw motion of S4 during which the salt bridge pattern between the S4 arginines and the negative charges of S1-S3 and of the lipid headgroups reorganizes. Together, this ratchet-like motion brings the VSD from the resting to the activated state in a series of jumps that proceed through several intermediate states. We use molecular dynamics simulations and free energy calculations to characterize the free energy landscape and the kinetic rates associated with the different steps of the activation process. To highlight the molecular determinants of this complex conformational transition, we apply techniques of machine learning and data analysis. Specifically, a custom-tailored dimensionality reduction approach is used to extract the relevant degrees of freedom describing the concerted motion of protein residues, lipids and waters.