Potential of Mean Force Between Ionizable Amino Acid Side Chains in Lipid Bilayer

Abstract

Potentials of mean force (PMF) between ionizable amino acid side chains (Arg, Lys, His, Glu/Asp) in different protonation states in palmitoyl oleoyl phosphatidylcholine lipid bilayer were obtained from all-atom explicit solvent molecular dynamics simulations and the adaptive biasing force approach available with NAMD.1,2 Side chains (SC) were constrained in different orientations: collinear, stacked and T-shaped and placed into the bilayer interface. The most structured PMFs were observed for unlike-charged ions or pairs with neutral SCs in collinear orientation. Contact pairs (CP) occurred at a distance of 2.6-3.1 A with the strongest interaction of −9.6 kcal/mol between Arg+ and Glu- ions. Like-charged SCs in this orientation displayed less stable contact minima at greater distances or solvent separated minima. All pairs in stacking approach showed similar, well-structured PMF profiles with CPs at ∼3.8 A. The strongest interaction between like-charged pairs was observed for stacked arginines. Like-charged pairs constrained in T-shaped geometry mostly displayed slightly stable solvent separated minima. A relationship between water and phosphate coordination numbers, contact pair minima and free energy barriers was found. There is also dependence of PMF shapes on H-bonding between amino acids. Generally, interactions between ionizable SCs are more attractive and the PMFs are more structured in a lipid bilayer than in water.31 Darve, E.; Pohorille, A. J. Chem. Phys. 2001, 115, 9169.2 Darve, E.; Wilson, M.; Pohorille, A. Mol. Simul.2002, 28, 113.3 Masunov, A.; Lazaridis, T.J. Am. Chem. Soc.2003125, 1722.