Protegrin-1 Orientation in Membrane Bilayers: Insights from Potential of Mean Force Calculations as A Function of Its Tilt and Rotation Angles

Abstract

Protegrin-1 (PG-1) belongs to the family of antimicrobial peptides. It interacts specifically with the membrane of a pathogen and kills the pathogen by releasing its cellular contents. To fully understand the energetics governing the orientation of PG-1 in different membrane environments and its effects on the physicochemical properties of the peptide, we have calculated the potentials of mean force (PMF) of PG-1 as a function of its tilt angle in explicit membrane bilayers composed of either DLPC (1,2-dilauroylphosphatidylcholine) or POPC (1-palmitoyl-2-oleoylphosphatidylcholine) lipid molecules. The resulting PMFs in explicit lipid bilayers were then used to search for the optimal hydrophobic thickness of the implicit membrane, in which a two-dimensional PMF in the tilt and rotation space was calculated. The calculated PMFs in explicit membrane systems clearly reveal that the energetically favorable tilt angle is affected by both the membrane hydrophobic thickness and the PG-1 rotation angle. Local thinning of the membrane around PG-1 is observed upon PG-1 tilting. The thinning effect is caused by different arginines in regard to the rotation orientation of the peptide. The two-dimensional PMF calculated in implicit membrane at specified rotation angles is in good accordance with those from the explicit membrane simulations. The ensemble-averaged Val16 15N and 13CO chemical shifts calculated from the two-dimensional free energy distribution agree fairly well with the experimental values, suggesting the accuracy and reliability of the application of PMFs to understand important physicochemical properties of membrane peptides/proteins.