Molecular dynamics of SLC26 transporters

溶质载体26(SLC26)家族膜蛋白由次级活性阴离子交换器、介导通道状阴离子转运的异构体和电压驱动的马达蛋白Prestin组成。SLC26转运蛋白的底物包括氯化物、碳酸氢盐、碘化物、硫酸盐、甲酸盐和草酸盐。SLC26转运蛋白参与多种生理过程，其功能障碍与多种疾病相关。例如，SLC26A3功能受损是先天性氯化物腹泻的基础，SLC26A11参与细胞毒性脑水肿，SLC26A9是囊性纤维化的重要疾病修饰物。尽管SLC26转运体是许多疾病治疗药物的潜在靶点，但SLC26转运体的结构机制--包括转运机制多样性和底物选择性的分子基础--尚不清楚，合理的药物开发也相对滞后。最近，SLC26Dg和SLC26a9的实验结构揭示了SLC26家族在近原子分辨率下保守的分子结构和二聚体排列，为高性能计算生物学技术揭示该家族的结构-动力学-功能关系提供了基础。通过对SLC26转运蛋白在近天然条件下的原子分子动力学模拟，我们的目标是描述底物和抑制剂结合的原理，识别热力学耦合和解偶联的阴离子转运机制，并建立SLC26二聚体亚基间协同作用的基础。我们的模拟将与我们研究单位内的电生理和冷冻电子显微镜实验密切合作，以验证从我们的模拟中获得的见解，并支持对实验数据的解释和为新的实验提供信息。因此，我们的目标是在原子分辨率上对必要的转运功能有一个有效的理解，并希望为合理的结构导向的SLC26转运体药物开发提供基础。

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.