Lipopeptide daptomycin: Interactions with bacterial and phospholipid membranes, stability of membrane aggregates and micellation in solution

Daptomycin is a cyclic lipopeptide effective against multidrug Gram-positive bacteria. Despite having a net negative charge, it is selective against negatively charged bacterial membranes. It has been established that daptomycin's antibiotic activity is based on directly targeting the bacterial membranes and that this antibacterial activity depends on calcium ions. Importantly, however, both the precise role of ions and the physical mechanisms responsible for daptomycin's action remain poorly understood. We investigate these issues using three types of molecular dynamics simulations: umbrella sampling free energy calculations for a single daptomycin, unbiased simulations for daptomycin tetramers, and unbiased simulations of micellation of daptomycin both in the absence and presence of calcium ions. The simulations are in the excess of 4 is. As the most important finding, we establish that binding of the calcium ions on the aspartic acid residues is the key to stabilizing daptomycin tetramers inside the model material membrane. These complexes are vital for daptomycin's antibacterial activity. In the absence of binding, the tetramer is not stable and moves slowly out of the membrane. We also demonstrate that in solution, micellation of daptomycin occurs both in the presence and absence of calcium ions, and discuss the similarities between the behaviors of daptomycin and amyloid peptides in membranes.