Anticorrelated position fluctuation of lipids in forming membrane water pores: molecular dynamics simulations study with dengue virus capsid protein

Abstract

The traffic of molecules into or out of cells is regulated by many membrane-associated mechanisms. Membrane pores are considered as one of the major passage mechanisms, although molecular-level understanding of pore formation is still vague. The opening of a membrane pore depends on many factors, including the influence of some proteins. The ability of the cell-penetrating peptides and supercharged proteins to form membrane pores has been reported. We studied pore formation through dipalmitoylphosphatidylcholine (DPPC) lipid bilayers by supercharged dengue virus capsid (C) protein. Atomistic molecular dynamics simulations confirmed the formation of membrane pores by a combined effect of the C protein and the membrane electric field. Analyses of simulated trajectories showed highly correlated vertical position fluctuations between the Cα atom of the membrane-anchored arginine residues and the phosphorus atoms of the surrounding DPPC lipids. Certain regions of the bilayer were negatively correlated while the others were positively correlated with respect to the fluctuations of the Cα atom of the anchored arginine residues. When positively correlated lipids in one leaflet vertically aligned with the negatively correlated lipids in the other leaflet, a local anticorrelated region was generated by weakening the bilayer. The membrane pore was always formed close to this anticorrelated region. Once formed, the C protein followed the hydrated pathway provided by the water-filled pores to cross the membrane. Communicated by Ramaswamy H. Sarma