Does arginine remain protonated in the lipid membrane? Insights from microscopic pKa calculations

Abstract

Free energy perturbation calculations are carried out to estimate the effective pK(a) of an arginine (Arg) sidechain as a function of its location in the dipalmitoylphosphatidylcholine bilayer. Similar to previous all-atom simulations of the voltage sensor domain of a potassium channel in the membrane with charged Arg residues, the membrane and water structures deform to stabilize the charge of the Arg analog. As a result, the computed pK(a) is >7 throughout the membrane although the value is very close to 7 near the center of the bilayer. With additional stabilizations from negatively charged amino acids or lipid molecules, it is reasonable to expect that Arg in membrane proteins (once in the membrane) can adopt the protonated state despite the low dielectric nature of the bulk lipid membrane.

FIGURE 1

The Arg analog used in the study; partial charges for the charged/neutral states are shown.

FIGURE 2

Computed pK_a value for an Arg analog in different locations in a DPPC bilayer from our (CHARMM) work and a recent potential of mean force study (6); z = 0.0 corresponds to the mid-plane of the bilayer. The solution pK_a is 12.48. (8).

FIGURE 3

Snapshots during the production run at z = 0 Å with a charged state, λ = 0.0, (left) and a neutral state, λ = 1.0 (right). ARG analog and P and N atoms are shown as sphere. Phosphorus is in orange and nitrogen in blue.

FIGURE 4

Cumulative distribution of phosphorus atom of lipid (left) and water (right) around a charged (upper)/neutral (lower) Arg sidechain (distance measured from its center of mass).