Free energy barrier for melittin reorientation from a membrane-bound state to a transmembrane state

An important step in a phospholipid membrane pore formation by melittin antimicrobial peptide is a reorientation of the peptide from a surface into a transmembrane conformation. In this work we perform umbrella sampling simulations to calculate the potential of mean force (PMF) for the reorientation of melittin from a surface-bound state to a transmembrane state and provide a molecular level insight into understanding peptide and lipid properties that influence the existence of the free energy barrier. The PMFs were calculated for a peptide to lipid (P/L) ratio of 1/128 and 4/128. We observe that the free energy barrier is reduced when the P/L ratio increased. In addition, we study the cooperative effect; specifically we investigate if the barrier is smaller for a second melittin reorientation, given that another neighboring melittin was already in the transmembrane state. We observe that indeed the barrier of the PMF curve is reduced in this case, thus confirming the presence of a cooperative effect

Passive membrane permeability: beyond the standard solubility-diffusion model

The spontaneous diffusion of solutes through lipid bilayers is still a challenge for theoretical predictions. Since permeation processes remain beyond the capabilities of unbiased molecular dynamics simulations, an alternative strategy is currently adopted to gain insight into their mechanism and time scale. This is based on a monodimensional description of the translocation process only in terms of the position of the solute along the normal to the lipid bilayer, which is formally expressed in the solubility-diffusion model. Actually, a role of orientational and conformational motions has been pointed out, and the use of advanced simulation techniques has been proposed to take into account their effect. Here, we discuss the limitations of the standard solubility-diffusion approach and propose a more general description of membrane translocation as a diffusion process on a free energy surface, which is a function of the translational and rotational degrees of freedom of the molecule. Simple expressions for the permeability coefficient are obtained under suitable conditions. For fast solute reorientation, the classical solubility-diffusion equation is recovered. Under the assumption that well-defined minima can be identified on the free energy landscape, a mechanistic interpretation of the permeability coefficient in terms of all possible permeation paths is given