Computational analysis of the structural and functional impact of the deleterious nsSNPs in the human F2R gene and their implications in glioma

The protease-activated receptor 1 (PAR1) protein, derived from the F2R gene, is integral to various physiological and pathological mechanisms and has been recognized as an oncogene in multiple studies, playing a crucial role in the aggressive and metastatic characteristics of cancer. However, no comprehensive investigation has yet been conducted on the possible impact of its missense mutations. In this study, we employed a computational pipeline to determine potentially deleterious nonsynonymous single-nucleotide polymorphisms (nsSNPs) within the F2R gene and evaluate their structural and functional impact on the PAR1 protein, as well as their association with cancer. PAR1 missense variants were primarily retrieved from the dbSNP database and Ensembl genome browser. Fifteen variants were subsequently predicted to exert detrimental effects using fourteen different computational tools. Phenotypic effect prediction, integrated with structural modeling, revealed that two variants (R214H and C378G) exert the most severe functional consequences, based on their location in highly conserved regions and their predicted ability to destabilize protein structure. Molecular docking analysis and subsequent molecular dynamics simulations demonstrated a destabilization of the two variants compared to the wild type, potentially leading to reduced protein activity. Furthermore, non-coding SNPs were predicted to alter regulatory elements of the F2R gene, influencing its expression across multiple tissues. Analysis of the F2R gene using TCGA data suggested its significant association with the progression and overall survival of low-grade glioma patients. These findings provide a foundation for future large-scale population studies and highlight the prospect of targeting PAR1 protein variants in cancer research and drug discovery, particularly in the context of precision medicine for glioma.