Microscopic insights into melittin induced changes in molecular dynamics of lipid bilayer membranes

Abstract

Melittin is an important antimicrobial peptide, and its membrane disruption mechanism has been attributed to its strong interaction with the cell membrane. Recently, Sharma et al. have investigated effects of melittin on the dynamics of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membrane using neutron scattering techniques. Their measurements showed that effects of melittin strongly depend on the physical state of the bilayers and the presence of cholesterol. In this study, extensive molecular dynamics (MD) simulations are performed on the DMPC lipid bilayers with and without cholesterol in the range of temperatures 275-315 K to investigate the effects of melittin on the microscopic dynamics of the membrane. Through the decomposition of membrane dynamics, our MD simulations suggest that in the fluid phase, the nanoscale membrane dynamics observed in the neutron experiments arises primarily from lateral diffusion, while in the gel phase, local internal motion plays an important role, accounting for 43.3%~60.7% of the total mean square displacement (MSD). Due to the different nature of the lateral diffusion and the local internal motion, how melittin affects the apparent membrane dynamics thus highly depends on the phase state of the membrane. In the fluid phase DMPC, the addition of melittin disrupts the lateral diffusion motion, leading to the overall hindered dynamics observed in experiment. However, the addition of melittin enhances the local internal motion slightly in the gel phase DMPC, giving rise to the apparent faster dynamics observed in experiment. In contrast, when 20% cholesterol is present, the bilayer abolishes the gel to fluid transition, the lateral diffusion is greatly suppressed across the entire experimental temperature range, exhibiting negligible differences in the membrane dynamics when melittin is added. Taken together, our simulations provide a unified mechanism for the effects of melittin on the DMPC bilayer dynamics both with and without cholesterol.