Effect of membrane thickness on conformational sampling of phospholamban from computer simulations

Abstract

The conformational sampling of monomeric, membrane-bound phospholamban is described from computer simulations. Phospholamban (PLB) plays a key role as a regulator of sarcoplasmic reticulum calcium ATPase. An implicit membrane model is used in conjunction with replica exchange molecular dynamics simulations to reach mus-ms timescales. The implicit membrane model was also used to study the effect of different membrane thicknesses by scaling the low-dielectric region. The conformational sampling with the membrane model mimicking dipalmitoylphosphatidylcholine bilayers is in good agreement overall with experimental measurements, but consists of a wide variety of different conformations including structures not described previously. The conformational ensemble shifts significantly in the presence of thinner or thicker membranes. This has implications for the structure and dynamics of PLB in physiological membranes and offers what we believe to be a new interpretation of previous experimental measurements of PLB in detergents and microsomal membrane.

Figure 1

Energy landscape for PLB in different membrane models; (A) MM1, (B) MM2, (C) MM3, and (D) MM4. Representative structures for the clusters corresponding to the minima are shown in cartoon representation. NMR structures with PDB codes 1N7L and 2KB7 are mapped and shown as red x and green o, respectively (15,16).

Figure 2

(A) Distribution of CP helix insertion. (B) Distribution of the TM helix (residues 25–52) insertion for different membrane models: MM1 (green solid line), MM2 (red dashed line), MM3 (blue dotted line), MM4 (black dash-dot line).