Molecular modeling of discoidal lipoprotein particles

Proteins and peptides containing amphipathic helices that have a characteristic charge distribution are capable of forming discoidal complexes with phospholipids. Discoidal complexes of this sort are formed naturally between apolipoprotein A-I and phospholipid in the life cycle of high-density-lipoprotein, and can be formed with other proteins and peptides containing amphipathic helices. These complexes consist of lipid bilayers with the non-polar phospholipid acyl chains protected from water by the helices. The helices in these discs have positively charged residues at the interface between the polar and non-polar faces, and negatively charged residues at the center of the non-polar face (Class A helices).; The structure and energetics of these discoidal particles are studied using molecular modeling. The interactions between charged residues, particularly salt-bridging, are observed to determine the orientation of different Apo A-I molecules relative to each other. Salt-bridging selects a particular low-energy structure from among the many which all have favorable distributions of hydrophobic and hydrophilic groups. In addition, molecular dynamics simulation is used to show that the synthetic class A helix forming peptide 18A forms stable discoidal complexes with phospholipid in which the helices are oriented perpendicular to the bilayer plane.; To evaluate the simulation procedure used for discoidal particles, and the time scales of processes in these systems, control or decoy simulations are used. MD simulations of 18A/phospholipid discoidal particles with reasonable distributions of hydrophobic and hydrophilic residues are compared to simulations in which the relative positions of these residues have been reversed. In the latter, decoy simulation, the helices have been rotated 180° so as to place the hydrophobic residues into water, and the hydrophilic residues in contact with phospholipid acyl chains. The results of the comparative simulations of an 18A/phospholipid particle and of the decoy structure indicate that the hydrophobic effect is well treated in these simulations. Hydrophobic residues prefer to minimize their contact with water. The structural origin of this effect is analyzed. Water molecules rapidly destabilize the decoy model through solvation of buried polar groups. Desolvation of exposed hydrophobic groups is slower. Global rearrangements of the decoy model occur on long time scales.