Membrane Association of Synaptotagmin 7 C2A Domain by Molecular Dynamics Simulations

Abstract

Synaptotagmin (Syt) acting as a calcium sensor promotes SNARE-mediated membrane fusion by docking to target membrane. Here we study the C2A domain of Syt7, which triggers Ca2+-dependent release of large dense-core vesicles in several cell types, by doing atomistic molecular dynamics simulations and Poisson-Boltzmann calculations. The association of the Syt7 C2A with membrane (POPC:POPS=3:1) was found accompanied by seesaw-like movements of the protein, primarily due to two significant interactions: (1) the electrostatic attractions between the negatively-charged lipid headgroups and the positively-charged residues in the loops L1-L3 and (2) the hydrophobic interactions between the lipid tails and a critical phenylalanine residue F167. Good linear correlation was found between the EPR measured penetration depth parameters and the theoretically calculated average penetration depths for a large number of residues.