Inter-ring rotation of apolipoprotein A-I protein monomers for the double-belt model using biased molecular dynamics

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. The salt bridge scoring indicated better energetic scoring in these alignments. 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. Here, we present computational data for independent inter-ring rotation of the two alpha-helical monomers about the lipid unilamellar bilayer core. The simulations presented here support the existing double-belt model. We find the rotation of the two protein monomers is able to occur with biasing. We determine that a cysteine mutant at Glu107 as a possible target for future mutational studies. Since HDL remodeling is necessary for cholesterol transport, our model for remodeling through dynamics has substantial biomedical implications.

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► Double-belt model for discoidal lipid-bound apo A-I's protein monomers may rotate independent of each other.
► MdMD scoring function used to bias MD dynamics.
► Energetics of inter-monomer proteins indicate possible mutants for experiment.
► Maintain proper apo A-I protein geometry while undergoing 360° rotation in under microsecond of sampling time with MD.