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 1000 ns-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 200 ns-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.
Document Object Identifier (DOI)
Cheng, K. H., Qiu, L., Cheng, S. Y., & Vaughn, M. W. (2015). Lipid insertion domain unfolding regulates protein orientational transition behavior in a lipid bilayer. Biophysical Chemistry, 206, 22-39. doi: 10.1016/j.bpc.2015.06.011