Disclosing Pathogenic Variant Effects on the Structural Dynamics of the VAPB MSP Domain Causing Familial ALS

Trajectory Dataset of Wild-Type and Pathogenic Variants of the VAPB MSP Domain Description: This dataset contains the trajectory data from molecular dynamics (MD) simulations of the wild-type and pathogenic variants of the vesicle-associated membrane protein (VAMP)-associated protein B (VAPB) major sperm protein (MSP) domain. The data were used in the manuscript entitled “Disclosing Pathogenic Variant Effects on the Structural Dynamics of the VAPB MSP Domain Causing Familial ALS”, published in the International Journal of Molecular Sciences (2025). [https://doi.org/10.3390/ijms26136489] The dataset includes complete 2.5-microsecond MD run data, with topology (.pdb) and trajectory (.dcd) files for the wild-type (WT) VAPB MSP domain and its pathogenic variants. The variants are P56S, P56H, and T46I, which are linked to the familial form of amyotrophic lateral sclerosis (ALS8). Files included: Wild.dcd and Wild.pdb: 2500 ns trajectory and topology data for the wild-type VAPB MSP domain. P56S.dcd and P56S.pdb: 2500 ns trajectory and topology data for the P56S variant, in which proline at position 56 is replaced by serine. P56H.dcd and P56H.pdb: 2500 ns trajectory and topology data for the P56H variant, in which proline at position 56 is replaced by histidine. T46I.dcd and T46I.pdb: 2500 ns trajectory and topology data for the T46I variant, in which threonine at position 46 is replaced by isoleucine. Background and purpose: VAPB is an endoplasmic reticulum (ER)-resident tethering protein. It recruits interacting partners to the ER surface and takes part in organelle membrane tethering, lipid transfer between organelles, calcium homeostasis, autophagy, and the unfolded protein response (UPR). Many of these interactions are mediated by the MSP domain, which binds proteins containing the FFAT (two phenylalanines in an acidic tract) motif. Pathogenic variants in the MSP domain cause ALS8, but the underlying pathophysiology remains unclear. These simulations were performed to examine how pathogenic variants change the structural dynamics of the VAPB MSP domain. The analyses showed that the variants altered the fluctuations and conformational dynamics of the protein. They also shifted the composition of secondary structure elements, increasing the proportion of α-helix and reducing β-sheet formation. These changes may affect organelle tethering and other VAPB functions, as well as VAPB homodimer and heterodimer formation.