Current concepts on the formation of discoidal apolipoprotein A-I lipid bound complexes: From picket fences to a double-belt model via inter-ring rotation of apolipoprotein A-I monomers

The double belt model for lipid-bound discoidal apolipoprotein A-I consists of two alpha-helical monomers bound about an unilamellar bilayer of lipids. Previous work, based on salt bridge calculations, has demonstrated that the L5/5 registration, Milano mutant, and Paris mutant are preferred conformations for apolipoprotein A-I. Additional recent research has indicated that there is a possibility of inter-ring rotation between the two monomers about the lipid unilamellar bilayer core. For instance, from well-known mutations, the Paris (R151C) and Milano (R173C) mutants indicate a mode of change must be available. To find proper registration, one proposed change is a 'rotationally' independent circular motion of the two protein monomers about the lipid unilamellar bilayer core. Current research shows that from a computational perspective, the independent inter-ring rotation of the two alpha-helical monomers about the lipid unilamellar bilayer core is feasible. And, such simulations support the existing double-belt model. Other long time scale dynamics simulations are very revealing of the discoidal behavior having preferred out-of-plane shapes akin to a saddle-point. However, despite all of the indicated deformations, the rotation of the two protein monomers is able to occur with biasing. It was determined that a cysteine mutant at Glu107 as a possible target for future mutational studies. Several other biophysical studies are discussed in light of these recent findings to bring a greater understanding to ApoA-I dynamic motion and registration shifts. Since HDL remodeling is necessary for cholesterol transport, our model for remodeling through dynamics has substantial biomedical implications.