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Simulating the interactions between per- and polyfluoroalkyl substances and kidney transporters for understanding
Yuyan Zhong1, Yulu Wang1, Yudan Dong1
1College of Public Health, Zhengzhou University, Zhengzhou, 450001, PR China.
Abstract:
Per- and polyfluoroalkyl substances (PFAS) exhibit prolonged renal retention and contribute to kidney injury, yet the molecular mechanisms governing their transporter-mediated clearance remain unclear. In this study, homology modeling, molecular docking, and computational tunnel analysis (CAVER 3.02 and CaverDock) were used to simulate the pathway of 13 PFAS through six key human kidney transporters (OAT1, OAT2, OAT3, OAT4, ABCG2, and MRP4). We identified and characterized functional tunnels in each transporter, and calculated key energy barriers (Emax: maximum binding energy; Ea: activation energy) during PFAS translocation. Results show that shorter chain PFAS (e.g., PFMOAA, PFBA) generally exhibited lower energy barriers than PFOA/PFOS during the basolateral uptake (OAT1/OAT2/OAT3), while most PFAS alternatives showed higher efflux efficiency than legacy PFAS during the apical efflux (ABCG2/MRP4). PFBS showed the highest reabsorption barrier of OAT4, which is related to its rapid elimination. The combination of Emax/Ea with PFAS-albumin dissociation constants (Kd) successfully predicted relative biological half-lives (e.g., PFOA < PFOS; PFBS < PFHxS). This work has established a comprehensive computational framework, which relates the structural characteristics of PFAS with transporter-specific transport compatibility, renal bioaccumulation, and half-life. The work also provides theoretical guidance for designing PFAS substitutes with low renal bioaccumulation and short half-life.
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