Molecular Details of the PH Domain of ACAP1 Protein Binding to PIP2-Containing Membranes

Abstract

ACAP1 protein dimers were previously reported to specifically bind to PIP2-containing cell membranes and form well-structured protein lattices in order to conduct membrane tubulation. We first carried out unrestrained molecular dynamics (MD) simulations to characterize orientation of the PH domains with respect to the BAR domains of the protein dimer. Owing to the atomic precision, we present a comprehensive orientation analysis of PH domain under different lipid-bound states. Furthermore, we sought to investigate nature of the two binding pockets on the PH domain revealed by our MD simulations. We performed additional restrained MD simulations and multiple PMF profiles of the two pockets were presented in order to account for their preference to PIP2 over other charged lipids, e.g. POPS lipids. Combining orientation analysis and studies of binding pockets, our simulations results reveal valuable molecular basis for protein-lipid interactions of ACAP1 proteins during membrane remodeling process.