Insights into Protegrin Antimicrobial Peptides Membrane Translocation by Multistep Molecular Dynamics Simulations

Protegrin-1 (PG-1) is a cationic arginine-rich antimicrobial peptide. It is known that PG-1 induces membrane disruption by forming a pore leading to cell death. However, the insertion mechanism for these highly cationic peptides into hydrophobic membrane environment is still poorly understood. The timescale for pore formation is in the range from minutes to hours, which is beyond the timescale of conventional MD simulations. It has been found that the arginine gaunidinium and lipid phosphate groups form a strong bidentate complex and is crucial for translocation. To investigate the role of the bidentate complex for PG-1 translocation, we applied MD simulations using different approaches to overcome the free energy barrier and timescale limitations. Electroporation was implemented to facilitate the translocation process. Potential of mean force calculations was performed to calculate the free energy of the bidentate complex insertion. Our results suggest that the complex alone is still unfavorable for PG-1 insertion inside hydrophobic environment. Pore formation may be the prerequisite for PG-1 translocation.