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

Abstract

AbstractMutations in VCP are responsible for 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. Till now, studies on disease phenotype relationship, structural, and functional modifications of the protein’s stability, phenotype, molecular dynamics, and post-translational modifications haven’t been performed. This in-silico study investigates the variants of VCP (R95C, R95G, A160P, R191P, R191Q) which have conflicting interests of pathogenicity and hence are often depreciated and lack data. In addition, this study screens the study cohort and the fatal diseases linked to all of 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. By VCP’s molecular dynamics simulations, its variation, deviation, compactness, flexibility, hydrogen bonds, and solvent accessibility were all comparatively impacted due to the changes caused by the variants. 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 investigate further the diseases linked with these variants and will be valuable to establish their specific roles and can further be used as biomarkers for fatal rare diseases.