PyLipID: A Python Package for Analysis of Protein–Lipid Interactions from Molecular Dynamics Simulations

Lipids play important modulatory and structural roles for membrane proteins. Molecular dynamics simulations are frequently used to provide insights into the nature of these protein-lipid interactions. Systematic comparative analysis requires tools that provide algorithms for objective assessment of such interactions. We introduce PyLipID, a python package for the identification and characterization of specific lipid interactions and binding sites on membrane proteins from molecular dynamics simulations. PyLipID uses a community analysis approach for binding site detection, calculating lipid residence times for both the individual protein residues and the detected binding sites. To assist structural analysis, PyLipID produces representative bound lipid poses from simulation data, using a density-based scoring function. To estimate residue contacts robustly, PyLipID uses a dual-cutoff scheme to differentiate between lipid conformational rearrangements whilst bound from full dissociation events. In addition to the characterization of protein-lipid interactions, PyLipID is applicable to analysis of the interactions of membrane proteins with other ligands. By combining automated analysis, efficient algorithms, and open-source distribution, PyLipID facilitates the systematic analysis of lipid interactions from large simulation datasets of multiple species of membrane proteins.

Molecular-dynamics simulations covering 30ns of both a natural and a synthetic antimicrobial peptide in the presence of a zwitterionic lipid bilayer were performed. In both simulations, copies of the peptides were placed in an α-helical conformation on either side of the bilayer about 10Å (1Å = 0.1nm) from the interface, with either the hydrophobic or the positively charged face of the helix directed toward the bilayer surface. The degree of peptide—lipid interaction was dependent on the starting configuration: surface binding and subsequent penetration of the bilayer was observed for the hydrophobically oriented peptides, while the charge-oriented peptides demonstrated at most partial surface binding. Aromatic residues near the N-termini of the peptides appear to play an important role in driving peptide—lipid interactions. A correlation between the extent of peptide—lipid interactions and helical stability was observed in the simulations. Insertion of the peptides into the bilayer caused a dramatic increase in the lateral area per lipid and decrease in the bilayer thickness, resulting in substantial disordering of the lipid chains. Results from the simulations are consistent with early stages of proposed mechanisms for the lytic activity of antimicrobial peptides. In addition to these ‘free’ simulations, 25ns simulations were carried out with the peptides constrained at three different distances relative to the bilayer interface. The constraint forces are in agreement with the extent of peptide—bilayer insertion observed in the free simulations.