Novel Lipid Dynamics Around the Cytolysin-A Membrane-Pore Complex and its Intermediates

Abstract

Pore forming toxins (PFTs) are ubiquitous weapons in the armoury of many organisms. It is often observed that small numbers of these potent proteins form stable pores, permeabilize the cell membrane and cause cell lysis. The complex role of the membrane in the formation of these pores, the influence of the pore on the structure and dynamics of the surrounding membrane and the expulsion of the central lipids upon pre-pore formation are important phenomena that are poorly understood due to the paucity of structural data.Multi-scale molecular dynamics was carried out on the PFT Cytolysin-A (ClyA), to address its interaction with the surrounding lipid membrane. A large heterogeneity in the lipid self-diffusivities were observed with the presence of more mobile and less mobile lipid fractions spanning the membrane. These results indicate that the local environment around the protein complex is markedly different from the rest of the membrane. Simulations of intermediate ClyA oligomers in a variety of membranes shows rapid evacuation of the central lipids from the interior to the free membrane surrounding the partially formed pore assembly. This implies that concerted lipid expulsion occurs prior to the formation of the dodecameric pore complex. This alternative hypothesis challenges the notion that destabilization and ejection of a membrane patch corresponding to the pore-lumen occurs after the pre-pore assembly on the membrane surface is complete. This mechanism could occur across PFT families and has implications on membrane resealing and cell recovery.