Scaling and Alpha-helix Regulation of Protein Relaxation in a Lipid Bilayer

Protein conformation and orientation in the lipid membrane play a key role in many cellular processes. Here we use molecular dynamics simulation to investigate the relaxation and C-terminus diffusion of a model helical peptide: beta-amyloid (A$\beta )$ in a lipid membrane. We observed that after the helical peptide was initially half-embedded in the extracellular leaflet of phosphatidylcholine (PC) or PC/cholesterol (PC/CHOL) membrane, the C-terminus diffused across the membrane and anchored to PC headgroups of the cytofacial lipid leaflet. In some cases, the membrane insertion domain of the A$\beta $ was observed to partially unfold. Applying a sigmoidal fit to the process, we found that the characteristic velocity of the C-terminus, as it moved to its anchor site, scaled with $\theta _{\mathrm{u}}^{-4/3}$, where $\theta_{\mathrm{u}}$ is the fraction of the original helix that was lost during a helix to coil transition. Comparing this scaling with that of bead-spring models of polymer relaxation suggests that the C-terminus velocity is highly regulated by the peptide helical content, but that it is independent of the amino acid type. The A$\beta $ was stabilized by the attachment of the positive Lys28 side chain to the negative phosphate of PC or 3$\beta $ oxygen of CHOL in the extracellular lipid leaflet and of the C-terminus to its anchor site in the cytofacial lipid leaflet.