元动力学
化学
运输机
分子动力学
基质(水族馆)
生物物理学
生物化学
生物
计算化学
基因
生态学
出处
期刊:Research Square - Research Square
日期:2023-04-06
标识
DOI:10.21203/rs.3.rs-2750967/v1
摘要
Abstract Human Na + taurocholate co-transporting protein (hNTCP) is a key bile salt transporter to maintain enterohepatic circulation and is responsible for the recognition of hepatitis B and D viruses (HBV/HDV). Despite recent cryo-EM studies revealing open-pore and inward-facing states of NTCP stabilized by antibodies, the transport mechanism remains largely unknown. Here, we use molecular dynamics (MD) and enhanced sampling Metadynamics simulations to elucidate the intrinsic mechanism of hNTCP-mediated taurocholate acid (TCA) transport driven by Na + -binding. We uncover three TCA binding modes, one of which closely matches the limited cryo-EM density observed in the open-pore hNTCP. Several key hNTCP conformations in the substrate transport cycle were captured, including an outward-facing, substrate-bound state. Furthermore, we provide thermodynamic evidence supporting that changes in the Na + -binding state drive the TCA transport by exploiting the amphiphilic nature of the substrate and modulating the protein environment, thereby enabling the TCA molecule to flip through. Understanding these mechanistic details of Na + -driven bile acid transport may aid in the development of hNTCP-targeted therapies for liver diseases.
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