Molecular dynamics simulations of monomeric apolipoprotein A-I from a recent X-ray structure

We have examined the X-ray crystal structure recently refined by Ajees and colleagues (Ajees et al. 2006) for monomeric apolipoprotein A-I (apoA-I). Because the structure, which has been crystallized together with chromium organic compounds, possesses a substantially higher percentage of alpha helicity than is generally estimated experimentally for the lipid-free monomeric apoA-I in solution (~80% vs ~50%), we have performed molecular dynamics (MD) simulations for ~10 ns of the model in order to explore the dynamic behavior of the single apoA-I monomer at a physiological salt concentration and a temperature range of 310-410 K. While 10 ns simulation is only a starting point, a few important observations have been made: i) the percentage of alpha helicity decreased substantially to below 70% (i.e., towards a lower experimental estimate); ii) the structure became more globular in overall appearance; iii) the flexible N-terminal domain (amino acid residues 1 to 43) has lost most of its alpha helicity; iv) the hydrophobic core of the 4-helix bundle is defined by stacking of a cluster of aromatic amino acid residues, outlined by a shell of aliphatic hydrophobic residues; v) The four helix bundle portion of the simulated structure is clustering around a pronounced stacking of aromatic residues derived from all four helixes and the aromatic cluster is overlaid by a shell of aliphatic hydrophobic residues. We conjecture that this aromatic cluster and its surrounding hydrophobic residues are the driving force for creation of a dynamic (molten globular) four helix bundle arrangement in lipid-free monomeric apoA-I in solution. This work was supported by NIH grant.