Free energy of lipid bilayer defects affected by Alzheimer's disease-associated amyloid-ß42 monomers.

Experimental evidence suggests that the amyloid ß-peptide (Aß) associated with Alzheimer's disease strongly disturbs the integrity of lipid bilayers and cell membranes, as a possible origin of the toxicity of this peptide. Here, we have used molecular dynamics simulations to compute the free energy of membrane pores in the presence and absence of Aß. The validation of our approach included the calculation of lipid flip-flop waiting times, which were found to agree well with recent experiments, in contrast with an earlier simulation study that apparently overestimated these waiting times. We find that, compared with peptide-free lipid bilayers, attached Aß42 peptides (i) increase the order parameters of the lipid tails but (ii) decrease the effective width of the hydrophobic region, (iii) reduce the free energy and thus enlarge the density of membrane pores, and (iv) increase the lifetime of pores. A detailed understanding of the interaction of Aß42 with lipid bilayer membranes may assist in the design of therapeutical strategies against Alzheimer's disease.

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. Experiments measure the fraction of peptides in the surface state and the transmembrane state, but no computational study exists that quantifies the free energy curve for the reorientation. 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 in understanding the peptide-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 increases. In addition, we study the cooperative effect; specifically we investigate if the reorientation barrier is smaller for a second melittin, given that another neighboring melittin was already in the transmembrane orientation. We observe that indeed the barrier of the PMF curve is reduced in this case, thus confirming the presence of a cooperative effect.