Membrane Insertion Profiles of Peptides Probed by Molecular Dynamics Simulations

Membrane insertion of small peptides plays important roles in antimicrobial defense, toxin actions, and viral infections. There have been experimental efforts to study this process with carefully designed synthetic peptides. Molecular dynamics simulation techniques are useful tools to study membrane insertion of peptides in atomic details to complement these experimental efforts. We developed a methodology based on molecular dynamics simulation techniques to probe the insertion profiles of small peptides across the membrane interface. The peptide is represented in full atomic detail, while the membrane and the solvent are described implicitly by a generalized Born model. To sample peptide conformations across the membrane interface, we apply an umbrella sampling technique, where the center of mass position of the peptide is constrained at various positions across the membrane interface. Free energy profiles are calculated as a function of the peptide position with respect to the membrane center and structural deviations from the native structure by the weighted histogram analysis method. We applied the methodology to a synthetic peptide mimicking the transmembrane domain of the M2 protein from influenza A virus. Two different initial peptide conformations, one fully extended and the other helical, have been used to probe the effect of peptide structures on the membrane insertion mechanism. A larger free energy decrease was observed when the peptide inserts into the membrane in a helical conformation than when it enters membrane in a nonhelical conformation. We discuss an improvement of the current methodology by increasing the sampling of peptide conformations with replica-exchange molecular dynamics simulations. With a growing number of bacterial infections that are resistant to conventional antibiotics, small peptides based on naturally-occurring antimicrobial peptides have become attractive candidates for a new class of antibiotics. The current methodology is expected to be useful in the design and engineering of therapeutic agents based on antimicrobial peptides with specific membrane-insertion profiles.