Lipid insertion domain unfolding regulates protein orientational transition behavior in a lipid bilayer

We have used coarse-grained (CG) and united atom (UA) molecular dynamics simulations to explore the mechanisms of protein orientational transition of a model peptide (Aβ42) in a phosphatidylcholine/cholesterol (PC/CHO) lipid bilayer. We started with an inserted state of Aβ42 containing a folded (I) or unfolded (II) K28-A42 lipid insertion domain (LID), which was stabilized by the K28-snorkeling and A42-anchoring to the PC polar groups in the lipid bilayer. After a UA-to-CG transformation and a 1000ns-CG simulation for enhancing the sampling of protein orientations, we discovered two transitions: I-to-“deep inserted” state with disrupted K28-snorkeling and II-to-“deep surface” state with disrupted A42-anchoring. The new states remained stable after a CG-to-UA transformation and a 200ns-UA simulation relaxation. Significant changes in the cholesterol-binding domain of Aβ42 and protein-induced membrane disruptions were evident after the transitions. We propose that the conformation of the LID regulates protein orientational transitions in the lipid membrane. [Display omitted] •Sampled beta-amyloid membrane orientational states by multiscale MD simulations•An initial inserted state had a folded (I) or unfolded (II) lipid insertion domain.•Discovered I-to-deep inserted and II-to-deep surface state transitions•Cholesterol-binding and bilayer structures were altered after the transition.•Lipid insertion domain regulates protein membrane orientational transitions.