In Silico Predictive Homology Modeling of PKHD-1 Protein: A Comparative Study among Three Different Species

Abstract

Abstract PKHD-1 (Polycystic Kidney and Hepatic Disease-1) gene encodes a vital pro- tein critical for renal and hepatic functions. Mutations in PKHD-1 lead to a severe type of disorder in early infancy called Autosomal Recessive Polycystic Kidney Disease (ARPKD). The PKHD-1 protein structure remains unavailable in databases such as PDB, with only a few low-resolution structures accessible in the Swiss Model Template Library. Therefore, Homology Modeling was employed to generate structural models of PKHD-1 proteins derived from three different species [Homo sapiens (Human), Mus musculus (Mouse), Canis lupus familiaris (Dog)]. The mouse PKHD-1 protein was structurally predicted by employing the AlphaFold DB model based on the PKHD1 ciliary IPT domain of fibro- cystin/polyductin from Rattus norvegicus as a reference template. Additionally, the human and dog PKHD-1 proteins were modeled using the AlphaFold DB model of the G8 domain-containing protein from Marmota monax as the template for the prediction process. In addition, we employ GOR4 for analyzing secondary structure, ProtParam for assessing physicochemical properties, QMEAN for eval- uating the quality of protein structure, and MolProbity for validating protein structures along with obtaining the Ramachandran plot. The binding pockets were also predicted using P2Rank tool (PrankWeb web server).