Abstract
Membrane nanopores are central players for a range of important cellular membrane remodeling processes as well as membrane rupture. Understanding pore formation in tense membranes requires comprehension of the molecular mechanism of pore formation and the associated free energy change as a function of the membrane tension. Here we propose a scheme to calculate the free energy change associated with the formation of a nanometer sized pore in molecular dynamics simulations as a function of membrane tension, which requires the calculation of only one computationally expensive potential of mean force. We show that membrane elastic theory can be used to estimate the pore formation free energy at different tension values from the free energy change in a relaxed membrane and the area expansion curves of the membranes. We have computed the pore formation free energy for a dipalmitoyl-phosphatidylcholine (DPPC) membrane at two different lateral pressure values, 1 bar and -40 bar, by calculating the potential of mean force acting on the head group of a single lipid molecule. Unrestrained simulations of the closing process confirm that the intermediate states along this reaction coordinate are reasonable and show that hydrophilic indentations spanning half the bilayer connected by a hydrophobic pore segment represent the corresponding high energy transition state. A comparison of the stability of simulated membranes to experiment at high loading rates show that, contrary to expectation, pores form too easily in small simulated membrane patches. This discrepancy originates from a combination of the absence of ions in the simulations and the small membrane size.
Highlights
Lipid bilayer membranes are essential for maintaining the structural integrity of cells, for the spatial organization of the cell interior and to serve as a scaffold for many proteins.[1]
To circumvent the high computational cost of estimating the free energy required to open a nanopore as a function of the membrane tension S by performing many potential of mean force (PMF) calculations, we propose the scheme illustrated in Fig. 1 and described below
In the simulations described here, a small hydrophilic pore shown in Fig. 2(a) forms when the phosphate group is restrained at z = 0 nm from the bilayer center
Summary
Lipid bilayer membranes are essential for maintaining the structural integrity of cells, for the spatial organization of the cell interior and to serve as a scaffold for many proteins.[1] To fulfill these roles, lipid membranes combine structural stability with flexibility allowing them to adjust to external forces. Lipid bilayers can form transient pores or rupture under mechanical, electrical or chemical stress Such pore formation plays an important role in many cellular processes that require membrane remodeling, ranging from protein insertion[2,3] to membrane fusion[4,5,6,7] and fission.[8,9] Beyond these cellular processes, controlled pore formation is important for biomedical applications such as drug delivery. Vast experimental as well as theoretical and computational efforts have been invested in understanding pore formation in lipid membranes
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