TMEM16 scramblases facilitate lipid permeation by membrane bending and lipid network interactions

The TMEM16 membrane protein family consists of both scramblases and ion channels involved in ol- faction, nociception, smooth muscle contraction, and blood coagulation. A scramblase is a membrane protein that conducts lipid headgroups from one leaflet to the other in a non specific and energy indepen- dent manner. The ion conduction pathway and the lipid conduction pathway in TMEM16 proteins are not known. Some researchers believe both may permeate the same path, but the precise mechanism of ion and lipid permeation is not clearly understood. This thesis is composed of two parts. In the first part, I develop methods that utilize continuum elasticity theory, electrostatics, and solvent accessible surface area calculations to explore resident protein interaction with the lipid bilayer. I test these methods on the well studied proteins, TRPV1 and Gramicidin, while adding insight to previous work. In the sec- ond part, I combine these methods with convention molecular dynamics simulations to understand lipid permeation in the Nectria hematococca TMEM16 scramblase. I identified specific residues on the pro- tein surface that are responsible for scrambling, and homologous positions in the mammalian TMEM16 family members may be promising pharmaceutical targets