Dataset Information

?-Secretase Studied by Atomistic Molecular Dynamics Simulations: Global Dynamics, Enzyme Activation, Water Distribution and Lipid Binding.

ABSTRACT: ?-secretase, an intramembrane-cleaving aspartyl protease is involved in the cleavage of a large number of intramembrane proteins. The most prominent substrate is the amyloid precursor protein, whose proteolytic processing leads to the production of different amyloid A? peptides. These peptides are known to form toxic aggregates and may play a key role in Alzheimer's disease (AD). Recently, the three-dimensional structure of ?-secretase has been determined via Cryo-EM, elucidating the spatial geometry of this enzyme complex in different functional states. We have used molecular dynamics (MD) simulations to study the global dynamics and conformational transitions of ?-secretase, as well as the water and lipid distributions in and around the transmembrane domains in atomic detail. Simulations were performed on the full enzyme complex and on the membrane embedded parts alone. The simulations revealed global motions compatible with the experimental enzyme structures and indicated little dependence of the dynamics of the transmembrane domains on the soluble extracellular subunits. During the simulation on the membrane spanning part a transition between an inactive conformation (with catalytic residues far apart) toward a putatively active form (with catalytic residues in close proximity) has been observed. This conformational change is associated with a distinct rearrangement of transmembrane helices, a global compaction of the catalytically active presenilin subunit a change in the water structure near the active site and a rigidification of the protein fold. The observed conformational rearrangement allows the interpretation of the effect of several mutations on the activity of ?-secretase. A number of long-lived lipid binding sites could be identified on the membrane spanning surface of ?-secretase which may coincide with association regions of hydrophobic membrane helices to form putative substrate binding exosites.

SUBMITTER: Hitzenberger M

PROVIDER: S-EPMC6328467 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

γ-Secretase Studied by Atomistic Molecular Dynamics Simulations: Global Dynamics, Enzyme Activation, Water Distribution and Lipid Binding.

Hitzenberger Manuel M Zacharias Martin M

Frontiers in chemistry 20190104

γ-secretase, an intramembrane-cleaving aspartyl protease is involved in the cleavage of a large number of intramembrane proteins. The most prominent substrate is the amyloid precursor protein, whose proteolytic processing leads to the production of different amyloid Aβ peptides. These peptides are known to form toxic aggregates and may play a key role in Alzheimer's disease (AD). Recently, the three-dimensional structure of γ-secretase has been determined via Cryo-EM, elucidating the spatial geo ...[more]

PMID: 30662893

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Project description:Human posttranslationally modified N-ras oncogenes are known to be implicated in numerous human cancers. Here, we applied a combination of experimental and computational techniques to determine structural and dynamical details of the lipid chain modifications of an N-ras heptapeptide in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membranes. Experimentally, 2H NMR spectroscopy was used to study oriented membranes that incorporated ras heptapeptides with two covalently attached perdeuterated hexadecyl chains. Atomistic molecular dynamics simulations of the same system were carried out over 100 ns including 60 DMPC and 4 ras molecules. Several structural and dynamical experimental parameters could be directly compared to the simulation. Experimental and simulated 2H NMR order parameters for the methylene groups of the ras lipid chains exhibited a systematic difference attributable to the absence of collective motions in the simulation and to geometrical effects. In contrast, experimental 2H NMR spin-lattice relaxation rates for Zeeman order were well reproduced in the simulation. The lack of slower collective motions in the simulation did not appreciably influence the relaxation rates at a Larmor frequency of 115.1 MHz. The experimental angular dependence of the 2H NMR relaxation rates with respect to the external magnetic field was also relatively well simulated. These relaxation rates showed a weak angular dependence, suggesting that the lipid modifications of ras are very flexible and highly mobile in agreement with the low order parameters. To quantify these results, the angular dependence of the 2H relaxation rates was calculated by an analytical model considering both molecular and collective motions. Peptide dynamics in the membrane could be modeled by an anisotropic diffusion tensor with principal values of Dparallel=2.1x10(9) s(-1) and Dperpendicular=4.5x10(5) s(-1). A viscoelastic fitting parameter describing the membrane elasticity, viscosity, and temperature was found to be relatively similar for the ras peptide and the DMPC host matrix. Large motional amplitudes and relatively short correlation times facilitate mixing and dispersal with the lipid bilayer matrix, with implications for the role of the full-length ras protein in signal transduction and oncogenesis.

Dataset Information

?-Secretase Studied by Atomistic Molecular Dynamics Simulations: Global Dynamics, Enzyme Activation, Water Distribution and Lipid Binding.

Publications

γ-Secretase Studied by Atomistic Molecular Dynamics Simulations: Global Dynamics, Enzyme Activation, Water Distribution and Lipid Binding.

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