title: All-atom accelerated molecular dynamics (aMD) simulations of Filamin-A (FLNa) actin-binding Domain, immunoglobulin-like Domains 3, 4, 5, 21 and 24 to investagate the impact of known missense mutations associated with periventricular nodular heterotopia in the liveborn males
author: Umut Gerlevik
description: Data includes all of the wild-type and mutant trajectories of accelerated all-atom molecular dynamics (aMD) simulations of Filamin-A (FLNa, the product of FLNA gene located on chromosome X). Wild-type proteins are from the PDB structures with IDs: 4M9P, 3HOP, 3CNK. The mutations, including R484Q that we discovered in a Turkish family, were formerly found in the liveborn males with FLNA-associated periventricular nodular heterotopia (PNH), who survived with the only copy of mutated FLNA. To understand how these mutations lead to the PNH and simultaneously allow their survival, we performed these MD simulations for the wild-type and mutant systems. Systems were prepared in Visual Molecular Dynamics (VMD 1.9.3) by placing them in a TIP3P water box with approximately 20 Å thickness from the protein surface and neutralizing the system by adding counter ions in the form of NaCl. Of note, only protein parts were kept for the submission to reduce the size of files. Nanoscale Molecular Dynamics (NAMD 2.13-CUDA) was used to perform MD simulations with CHARMM36m force field. For pressure and temperature controls, Nosé-Hoover Langevin barostat and Langevin thermostat were used. ShakeH algorithm of NAMD was applied for water molecule constraints. 12 Å cut-off distance was used for van der Waals interactions. Switching function starts at 10 Å and reaches zero at 14 Å. Integration time-step was 2 fs. To compute the long-range Coulomb interactions, the particle-mash Ewald method was used. After a 10000-step minimization with conjugate gradient algorithm and an equilibration for 1 ns at 298 K under NVT ensemble, production simulations were run along 100 ns. Only the production simulations were supplied in this dataset. Further details are available in the regarding configuration files. Resulting analysis files and scripts are included with the carbon alpha-containing dcd files of the simulations. This dataset is not used directly for any study, but they are preliminary results for the usage of aMD to understand rare disease mechanisms. Related publications: Zenodo repo of classical MD for these variants: https://doi.org/10.5281/zenodo.4483108 Journal article based on classical MD: Gerlevik U, Saygı C, Cangül H, Kutlu A, Çaralan EF, Topçu Y, et al. (2022) Computational analysis of missense filamin-A variants, including the novel p.Arg484Gln variant of two brothers with periventricular nodular heterotopia. PLoS ONE 17(5): e0265400. https://doi.org/10.1371/journal.pone.0265400