In silico Study of the Uncertainly Significant VCP Variants reveal major Structural, Functional fluctuations leading to potential Disease-Based Associations

Valosin containing protein is involved in a plethora of crucial functions from proteostasis, stress granule clearance to genome maintenance and ubiquitination. Hence, mutations in VCP can lead to a plethora of fatal diseases like Amyotrophic Lateral Sclerosis, Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1, Spastic paraplegia, Charcot-Marie-Tooth disease type 2Y, Dementia, and Osteitis Deformans to name a few. Studies on VCP disease phenotype relationship, structural, and functional modifications of the protein stability, conservation, molecular dynamics, and post-translational modifications have not been performed. This in silico study investigated the variants of VCP (R95C, R95G, A160P, R191P, R191Q) which have conflicting interpretations of pathogenicity which are often depreciated and lack data. Additionally, this study screened the study cohort and the fatal diseases linked to all these variants. Interestingly, through various computational tools and disease-based population studies, it was found that these variants are often found in patients linked with fatal diseases. The protein-protein interaction showed UFD1 has a direct association with VCP. The physicochemical parameters showed that A160P had the highest fluctuations of all the variants. Protein secondary structure, molecular dynamics simulations of RMSD, RMSF, RoG, hydrogen bonds, and solvent accessibility were all comparatively impacted due to the changes caused by the variants of VCP. Box-plot and Principal component analysis of the MD simulations visualized the changes in the wild type of the protein. Research in wet labs and screening of patient cohorts is necessary to further characterize the diseases linked with these variants. This study can potentially lead to the identification of biomarkers for fatal rare diseases. ### Competing Interest Statement The authors have declared no competing interest.