Molecular dynamics of SLC26 transporters

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The Solute Carrier 26 (SLC26) family of membrane proteins consists of secondary active anion exchangers, isoforms that mediate channel-like anion transport, and the voltage-driven motor protein prestin. Substrates of SLC26 transporters include chloride, bicarbonate, iodide, sulfate, formate, and oxalate. SLC26 transporters are involved in a variety of physiological processes, and their dysfunction is associated with several diseases. For example, impaired function of SLC26A3 underlies congenital chloride diarrhea, SLC26A11 is involved in cytotoxic brain edema, and SLC26A9 is an important disease modifier of cystic fibrosis. Although SLC26 transporters are potential targets of therapeutic agents in many diseases, the structural mechanisms of SLC26 transporters—including the molecular underpinnings of the diversity of transport mechanisms and substrate selectivities—are unknown, and rational drug development has lagged behind. Recently, experimental structures of SLC26Dg and Slc26a9 revealed the conserved molecular architecture and the dimeric arrangement of the SLC26 family at near-atomic resolution and now provide a basis for high-performance computational biology techniques to uncover the structure–dynamics–function relationships in this family of transporters. Using state-of-the-art atomistic molecular dynamics simulations of SLC26 transporters under near-native conditions, we aim to describe the principles of substrate and inhibitor binding, to identify the mechanisms of thermodynamically coupled and uncoupled anion transport, and to establish the basis of inter-subunit cooperativity in SLC26 dimers. Our simulations will be performed in close collaboration with electrophysiological and cryo-electron microscopy experiments within our research unit to validate insights obtained from our simulations, as well as to support interpretation of experimental data and to inform novel experiments. Thereby, we aim at a validated understanding of essential transport functions at atomic resolution and would like to provide a basis for rational structure-guided drug development on SLC26 transporters.