Early stages in Ab1-42 spontaneous aggregation: an unbiased dataset from coarse-grained molecular dynamics simulations.

Description

Soluble oligomers of Aβ-1-42 are widely recognized as crucial targets for the design of inhibitors for potential therapeutic intervention against Alzheimer´s disease. However, the intrinsically disordered character of this polypeptide poses serious difficulties for the experimental determination of conserved structural motifs. Indeed, initial aggregation steps are extremely challenging for state-of-the-art experimental techniques. Although molecular dynamics simulations harbor the potential to capture such initial association events, unbiased exploration of the conformational landscape available to unstructured dimers implies a significant computational cost. Here, we provide a dataset of configurations of Aβ1-42 dimers obtained by coarse-grained molecular dynamics (MD) simulations using the SIRAH force field. Trajectories are provided in standard gromacs format and can be easily converted to fully atomistic representations for visualization and analysis using molecular visualization/analysis software. The dataset contains MD trajectories of Aβ1-42 that undergo spontaneous and unbiased dimerization. We provide the time series of 25 replicates simulated for 10 microseconds under room conditions and physiological salt concentration. These multiple aggregation events provide valuable information not only on new binding pockets formed by the dimeric interface but also monomeric hot spots that can be targeted by small molecules on high-throughput docking campaigns. Alternatively, Aβ1-42 dimers could be used as aggregation seeds in studies of Aβ secondary nucleation.

Steps to reproduce

A detailed description of the protocol followed to generate the primary data is detailed in the paper published by our group "Dissecting the role of glutamine in seeding peptide aggregation, DOI: 10.1016/j.csbj.2021.02.014"⁠. Briefly, we employed the Xray PDB structure: 1IYT as initial coordinates for Aβ1-42 monomers. The peptide was mapped to coarse-grain using SIRAH Tools [DOI: 10.1093/bioinformatics/btw020]⁠, and solvated, NaCl ions were added to a concentration of 150 mM. MD simulations were performed in the NPT ensemble at 1 atm, generating randomized conformations by heating up to 373 K and cooling down to 300 K in consecutive steps, using the SIRAH force field version 2.0 [DOI: 10.1021/acs.jctc.9b00006]⁠ and GROMACS 2018.4 as simulation engine⁠. We then selected conformers from the 3 most populated clusters, using GROMACS gmx cluster analysis tool, with a 0.1 nm cutoff choosing the gromos clustering algorithm. For the dimerization simulations we distributed two monomers with distances of 5 nm between their geometric centers, using random orientations, giving a total of 54 simulation systems. MD simulations at 300 K were held for 1 μs and those systems forming stable dimeric structures were selected to extend their simulation time for other 10 μs.

Institutions

Categories

Funding

Licence