Comparison of coarse-grained (MARTINI) and atomistic molecular dynamics simulations of and toxin nanopores in lipid membranes

Pore forming toxins (PFTs) are virulent proteins whose primary goal is to lyse target cells by unregulated pore formation. Molecular dynamics simulations can potentially provide molecular insights on the properties of the pore complex as well as the underlying pathways for pore formation. In this manuscript we compare both coarse-grained (MARTINI force-field) and all-atom simulations, and comment on the accuracy of the MARTINI coarse-grained method for simulating these large membrane protein pore complexes. We report 20 long coarse-grained MARTINI simulations of prototypical pores from two different classes of pore forming toxins (PFTs) in lipid membranes - Cytolysin A (ClyA), which is an example of an toxin, and -hemolysin (AHL) which is an example of a toxin. We compare and contrast structural attributes such as the root mean square deviation (RMSD) histograms and the inner pore radius profiles from the MARTINI simulations with all-atom simulations. RMSD histograms sampled by the MARTINI simulations are about a factor of 2 larger, and the radius profiles show that the transmembrane domains of both ClyA and AHL pores undergo significant distortions, when compared with the all-atom simulations. In addition to the fully inserted transmembrane pores, membrane-inserted proteo-lipid ClyA arcs show large shape distortions with a tendency to close in the MARTINI simulations. While this phenomenon could be biologically plausible given the fact that -toxins can form pores of varying sizes, the additional flexibility is probably due to weaker inter-protomer interactions which are modulated by the elastic dynamic network in the MARTINI force-field. We conclude that there is further scope for refining inter-protomer contacts and perhaps membrane-protein interactions in the MARTINI coarse-grained framework. A robust coarse-grained force-field will enable one to reliably carry out mesoscopic simulations which are required to understand protomer oligomerization, pore formation and leakage.