Novel Changes in Discoidal High Density Lipoprotein Morphology: A Molecular Dynamics Study

AbstractApoA-I is a uniquely flexible lipid-scavenging protein capable of incorporating phospholipids into stable particles. Here we report molecular dynamics simulations on a series of progressively smaller discoidal high density lipoprotein particles produced by incremental removal of palmitoyloleoylphosphatidylcholine via four different pathways. The starting model contained 160 palmitoyloleoylphosphatidylcholines and a belt of two antiparallel amphipathic helical lipid-associating domains of apolipoprotein (apo) A-I. The results are particularly compelling. After a few nanoseconds of molecular dynamics simulation, independent of the starting particle and method of size reduction, all simulated double belts of the four lipidated apoA-I particles have helical domains that impressively approximate the x-ray crystal structure of lipid-free apoA-I, particularly between residues 88 and 186. These results provide atomic resolution models for two of the particles produced by in vitro reconstitution of nascent high density lipoprotein particles. These particles, measuring 95Å and 78Å by nondenaturing gradient gel electrophoresis, correspond in composition and in size/shape (by negative stain electron microscopy) to the simulated particles with molar ratios of 100:2 and 50:2, respectively. The lipids of the 100:2 particle family form minimal surfaces at their monolayer-monolayer interface, whereas the 50:2 particle family displays a lipid pocket capable of binding a dynamic range of phospholipid molecules

The leader peptides from bacteriorhodopsin and halorhodopsin are potential membrane-spanning amphipathic helices

AbstractWe show that the N-terminal leader peptides from the bacterial membrane proteins bacteriorhodopsin and halorhodopsin can be expected to form amphipathic α-helices with a highly hydrophobic nonpolar face and a narrow, negatively charged polar face. This finding is discussed in terms of a model for the integration of these proteins into the bacterial membrane

A robust all-atom model for LCAT generated by homology modeling

LCAT is activated by apoA-I to form cholesteryl ester. We combined two structures, phospholipase A2(PLA2) that hydrolyzes the ester bond at the sn-2 position of oxidized (short) acyl chains of phospholipid, and bacteriophage tubulin PhuZ, as C- and N-terminal templates, respectively, to create a novel homology model for human LCAT. The juxtaposition of multiple structural motifs matching experimental data is compelling evidence for the general correctness of many features of the model: i ) The N-terminal 10 residues of the model, required for LCAT activity, extend the hydrophobic binding trough for the sn-2 chain 15-20 \uc3\u85 relative to PLA2. ii ) The topography of the trough places the ester bond of the sn-2 chain less than 5 \uc3\u85 from the hydroxyl of the catalytic nucleophile, S181. iii ) A\uce\ub2 -hairpin resembling a lipase lid separates S181 from solvent. iv ) S181 interacts with three functionally critical residues: E149, that regulates sn-2 chain specifi city, and K128 and R147, whose mutations cause LCAT defi ciency. Because the model provides a novel explanation for the complicated thermodynamic problem of the transfer of hydrophobic substrates from HDL to the catalytic triad of LCAT, it is an important step toward understanding the antiatherogenic role of HDL in reverse cholesterol transport. -Segrest, J. P., M. K. Jones, A. Catte, and S. P. Thirumuruganandham. A robust all-atom model for LCAT generated by homology modeling