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

Abstract

Abstract: 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 μs 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 α toxin, and α-hemolysin (AHL) which is an example of a β 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 α-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. Graphical Abstract:: SYNOPSIS Multimeric and non-selective transmembrane pores formed by bacterial toxins on the host cell cause cell death, and hence elucidating membrane-protein interactions accurately in molecular models is important for unraveling biological phenomena at molecular resolution. A comparison of coarse-grained (MARTINI) and all-atom simulations for two prototypical pores in lipid membranes show that the transmembrane domains of both pores undergo significant distortions in MARTINI but not in all-atom simulations. Additionally, transmembrane proteo-lipid arcs show large shape distortions with a tendency to close in the MARTINI simulations. This indicates that both inter-protein and membrane-protein interactions in the MARTINI framework must be refined further.[Figure not available: see fulltext.].