We performed a series of molecular dynamics simulations to study the nature of interactions between transportan 10 (tp10) and a zwitterionic POPC bilayer. Tp10 is an amphipathic cell-penetrating peptide with a net positive charge of +5 and is known to adopt an a-helical secondary structure on the surface of POPC membranes. The study showed that tp10 preferentially binds to the membrane surface with its hydrophobic side facing the hydrophobic lipid core. Such orientation allows Lys residues, with positively charged long side chains, to stay in the polar environment during the insertion process. The simulations revealed that the Lys phosphate salt bridge is a key factor in determining the orientation of the peptide in the interfacial region as well as in stabilizing the peptide membrane interaction. The electrostatic attraction between Lys and phosphate groups is also believed to be the main bottleneck for the translocation of tp10 across the membrane.