Computational analysis of Non-synonymous SNP effects on human PLVAP gene structure and function

Plasmalemma vesicle-associated protein (PLVAP) plays a pivotal role in regulating endothelial permeability and maintaining blood-brain barrier (BBB) integrity. As a cellular receptor for the Japanese Encephalitis Virus (JEV) envelope protein, PLVAP significantly influences viral neuroinvasion and central nervous system entry. This study employed computational approaches to investigate the functional impact of non-synonymous single-nucleotide polymorphisms (nsSNPs) in the PLVAP gene and their potential effects on JEV-host interactions. We retrieved 11,883 SNPs from the NCBI dbSNP database and identified 403 unique nsSNPs for comprehensive analysis. Approximately 50% of these variants resulted in alterations to amino acid charge or polarity, indicating potential functional consequences. Stability analysis revealed 43 nsSNPs that significantly destabilized PLVAP structure (ΔΔG ≤ -1 kcal/mol), with several variants also affecting local protein disorder. Conservation analysis identified 29 deleterious nsSNPs, emphasizing their evolutionary importance and functional relevance. Five critical variants (R26H, I35T, E175G, V44G, and I39S) were prioritized based on their pronounced destabilizing effects on PLVAP structure and function. Molecular docking studies demonstrated that these mutations substantially altered PLVAP-JEV envelope protein binding interactions, potentially modifying viral entry efficiency and host susceptibility. These findings suggest clinical applications, including the use of PLVAP variants as biomarkers for risk stratification and guiding vaccination strategies in endemic regions. Moreover, insights into PLVAP-JEV interactions open avenues for therapeutic interventions, such as small-molecule inhibitors targeting viral entry. This computational framework may be extended to other flavivirus-host interactions, advancing antiviral drug discovery and personalized medicine approaches for JEV prevention.