Computational Exploration of Protein Structure Dynamics and RNA structural Consequences of PKD1 Missense Variants: Implications in ADPKD Pathogenesis

Autosomal dominant polycystic kidney disease (ADPKD), a genetic disorder characterized by the formation of fluid-filled cysts within the kidneys, leading to progressive renal dysfunction, is primarily caused by mutations in PKD1, a gene encoding for the protein polycystin-1 (PC1). Understanding the structural consequences of PKD1 variants is crucial for elucidating disease mechanisms and developing targeted therapies. In this study, we analyzed the effects of nine missense PKD1 variants, including c.6928G>A p.G2310R, c.8809G>A p.E2937K, c.2899T>C p.W967R, c.6284A>G p.D2095G, c.6644G>A p.R2215Q, c.7810G>A p.D2604N, c.11249G>C p.R3750P, c.1001C>T p.T334M, and c.3101A>G p.N1034S on RNA structures, their interactions utilizing computational tools. We also explain the effects of these variants on PC1 protein dynamics, stability, and interactions using molecular dynamics (MD) simulation. These variants are located at crucial domains such as the REJ domain, PKD domains, and cation channel domain, potentially compromising PC1s function and contributing to ADPKD pathogenesis. Findings reveal substantial deviations in RNA structures and their interactions with other proteins or RNAs and also protein structure and dynamics for variants such as c.8809G>A (p.E2937K), c.11249G>C (p.R3750P), c.3101A>G (p.N1034S), c.6928G>A (p.G2310R), c.6644G>A (p.R2215Q) suggesting their potential implications in disease etiology. The study also suggests that although certain variants may have minimal effects on RNA conformations, their observed alterations in MD simulations indicate potential impact on protein structure dynamics highlighting the importance of evaluating the functional consequences of genetic variants by considering both RNA and protein levels. This study offers valuable perspectives of the utility of studying the structure dynamics through computational tools in prioritizing the variants for their functional implications and understanding the molecular mechanisms underlying ADPKD pathogenesis and developing therapeutic interventions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/586139v1_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@4623f0org.highwire.dtl.DTLVardef@e186a1org.highwire.dtl.DTLVardef@4deffaorg.highwire.dtl.DTLVardef@c60744_HPS_FORMAT_FIGEXP M_FIG C_FIG