Biomedical subjects

Marcela P Aliste

Publications and source records attributed to Marcela P Aliste.

3 recordsLinked to original sources

PubMed2006

Novel changes in discoidal high density lipoprotein morphology: a molecular dynamics study.

ApoA-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 95 angstroms and 78 angstroms 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.

Apolipoprotein A-I↗

PubMed2005

Computer simulation of partitioning of ten pentapeptides Ace-WLXLL at the cyclohexane/water and phospholipid/water interfaces.

BACKGROUND: Peptide-membrane interactions play a key role in the binding, partitioning and folding of membrane proteins, the activity of antimicrobial and fusion peptides, and a number of other processes. To gain a better understanding of the thermodynamics of such interactions, White and Wimley created an interfacial hydrophobicity scale based of the transfer free energy from water to octanol or lipid bilayers of a series of synthetic peptapeptides (Ace-WLXLL, with X being any of the twenty natural amino acids) (White and Wimley (1996) Nat. Struct. Biol. 3, 842-848). In this study, we performed molecular dynamics simulations of a representative set of ten of these peptides (X = D, K, R, N, A, T, S, I, F and W) in two membrane mimetic interfaces: water-cyclohexane (10 ns) and a fully solvated dioleoylphosphatidylcholine (DOPC) bilayer (50 ns) using both constant pressure and constant area ensembles. We focus on partitioning of the ten peptides at the cyclohexane/water and lipid/water interfaces. RESULTS: The peptides rapidly equilibrate (< 2 ns) and partition at the cyclohexane/water interface. The X3 guest residue assumes average orientations that depend on the nature of the side chain. At the DOPC/water interface, dynamics is much slower and convergence is difficult to achieve on a 50 ns timescale. Nonetheless, all peptides partition to the lipid/water interface with distributions with widths of 1-2 nm. The peptides assume a broad range of side chain and backbone orientations and have only a small effect on the area of the unit cell. On average, hydrophobic guest residues partition deeper into the hydrophobic core than hydrophilic residues. In some cases the peptides penetrate sufficiently deep to somewhat affect the distribution of the C=C double bond in DOPC. The relative distribution of the X3 guest residue compared to W1 and L5 is similar in the water/cyclohexane and water/lipid simulations. Snapshots show mostly extended backbone conformations in both environments. There is little difference between simulations at a constant area of 0.66 nm2 and simulations at constant pressure that approximately yield the same average area of 0.66 nm2. CONCLUSION: These peptides were designed to assume extended conformations, which is confirmed by the simulations. The distribution of the X3 side chain depends on its nature, and can be determined from molecular dynamics simulations. The time scale of peptide motion at a phospholipids-water interface is too long to directly calculate the experimentally measured hydrophobicity scale to test and improve the simulation parameters. This should be possible at the water/cyclohexane interface and likely will become feasible in the future for the phospholipids/water case.

Amino Acid Sequence↗

PubMed2003

Molecular dynamics simulations of pentapeptides at interfaces: salt bridge and cation-pi interactions.

Peptide-membrane interactions are important for understanding the binding, partitioning, and folding of membrane proteins; the activity of antimicrobial and fusion peptides; and a number of other processes. We describe molecular dynamics simulations (10-25 ns) of two pentapeptides Ace-WLXLL (with X = Arg or Lys side chain) (White, S. H., and Wimley, W.C. (1996) Nat. Struct. Biol. 3, 842-848) in water and three different membrane mimetic systems: (i) a water/cyclohexane interface, (ii) water-saturated octanol, and (iii) a solvated dioleoylphosphatidylcholine bilayer. A salt bridge is found between the protonated Arg or Lys side chains with the carboxyl terminus at the three interfaces. In water/cyclohexane, the salt bridge is most exposed to the water phase and least stable. In water/octanol and the lipid bilayer systems, the salt bridge once formed persists throughout the simulations. In the lipid bilayer, the salt bridge is more stable when the peptide penetrates deeper into the bilayer. In one of two peptides, a cation-pi interaction between the Arg and the Trp side chains is stable in the lipid bilayer for about 15 ns before breaking. In all cases, the conformations of the peptides are restricted by their presence at the interface and can be assigned to a few major conformational clusters. Side chains facing the water phase are most mobile. In the lipid bilayer, the peptides remain in the interface area, where they overlap with the carbonyl area of the lipid bilayer and perturb the local density profile of the bilayer. The tryptophan side chain remains in the water-lipid interface, where it interacts with the lipid choline group and forms hydrogen bonds with the ester carbonyl of the lipid and with water in the interface.

Arginine↗