Computational protocol: Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies

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Protocol publication

[…] Two different models for the Aβ1–42 species were considered: the U-shaped Aβ17–42 (PDB ID: 2BEG []) and the recently resolved S-shaped Aβ11–42 (PDB ID: 2MXU []). Starting models are also reported in . A pentamer of Aβ17–42 was extracted from each PDB structure. In the manuscript the considered pentamers are called, the U-shaped model (Aβ17–42 pentamer extracted from 2BEG.pdb []) and the S-shaped model (Aβ17–42 pentamer extracted from 2MXU.pdb []).The U-shaped and the S-shaped models were solvated in a cubic box with each side equal to 6 nm and neutralized by counterions. Each system consisted of about 21,000 interacting particles. The AMBER99SB-ILDN force field [] was used to define protein topologies and the TIP3P model [] was used to represent the water molecules. The systems were first minimized by applying the steepest descent energy minimization algorithm, followed by preliminary simulation in NVT ensemble (constant Number of particles, Volume, and Temperature) of 50 ps duration. V-rescale thermostat was applied to keep temperature at 300 K with a time constant of 0.1 ps []. An additional simulation in NPT ensemble (constant Number of particles, Pressure, and Temperature) of 50 ps duration was carried out at 300 K (τ = 1 ps) and 1 atm (τ = 5 ps). V-rescale [] and Berendsen [] coupling methods were used as temperature and pressure coupling. Then, 100 replicas were generated with temperatures ranging from 280 to 558 K and distributed applying the exponential spacing strategy, as previously done in literature [,]. A first NVT position restrained MD was run on each replica for 50 ps. Finally, a 60 ns of production NVT-REMD was carried out on each replica at its own temperature, according to previous works []. The replica exchange interval was set equal to 1 ps, large enough if compared to the time constant of the heath bath (τ = 0.1 ps). The resulting exchange probability was 0.3. The computational data were time-averaged over all trajectory steps corresponding to the chosen temperature, 300 K in this work. The LINCS algorithm [] was used to constrain the lengths of all bonds. The integration time step was 2 fs. Periodic boundary conditions were applied along xyz. The short-range Van der Waals (VDW) and electrostatics interactions were cut off after 1 nm; the Particle Mesh Ewald (PME) method [] was employed for long-range electrostatics. GROMACS 5 was used for REMD simulations and data analysis []. The inter-chain protein contacts were identified by contact probability plots. Contact probability for each residue was calculated as already described in a previous work []. […]

Pipeline specifications

Software tools ProTop, P-LINCS, GROMACS
Application Membrane protein analysis
Diseases Alzheimer Disease, Neurodegenerative Diseases, Drug-Related Side Effects and Adverse Reactions