(111e) Dimerization of Protegrin-1 Peptides in Different Environments

Molecular dynamics simulations are used to study the dimerization of the cationic antimicrobial peptide protegrin-1 (PG1) in three different environments: water, the surface of lipid bilayer membranes, and the core of the lipids. PG1 is known to kill bacteria by forming oligomeric membrane pores, which permeabilize the cells. PG1 dimers, prevalently in two distinct, parallel and antiparallel conformations, have been found to be important structural units that appear as intermediates of the oligomeric active structures. What is not clear, is the sequence of events that PG1 follows from monomers in solution to pores inside membranes. The step we focus on in this work is the dimerization of PG1. In particular, we are interested in determining where is PG1 dimerization most favorable. We use extensive molecular dynamics simulations to determine the potential of mean force as a function of distance between two PG1 monomers in three different environments: the water subphase, the surface of model lipid bilayers and the lipid membranes.

We investigate the two known, distinct modes of dimerization that result in either a parallel or an antiparallel one. The model bilayer membranes are composed of anionic palmitoyl-oleoyl-phosphatidylglycerol (POPG) and palmitoyl-oleoyl-phosphatidylethanolamine (POPE) with ratio 1:3 (POPG:POPE).

We find the parallel PG1 dimer association to more favorable than the antiparallel one in water and inside the membrane. However, we observe that the antiparallel dimer conformation is somewhat more stable than the parallel dimer association at the surface of the membrane. We explore the role of hydrogen bonds, ionic bonds, salt bridges in peptide dimerization in water, at the surface of the membrane and inside membrane. The findings are suggestive of the dominant pathways between individual PG1 molecules in solution and functional pores inside bacterial membranes.