Dynamics of the splicing factor SRSF6 protein show metastable conformations with potentially druggable sites revealed by Markov state model

Abstract

The splicing factor SRSF6 has emerged as a promising target for cancer treatment. In order to gain a comprehensive understanding of the structure and dynamics of SRSF6 and identify the potential binding sites of inhibitors, a combined approach of microseconds-time scale molecular dynamics simulations and Markov state models, followed by molecular docking, was employed here. We predicted that SRSF6 protein exhibits a variety of characteristic metastable conformations that are stabilized by specific hydrogen bonds and/or salt bridges formed between the RRM domains and the loop linker. The transitions between the metastable states are in the time scales ranging from nanoseconds to microseconds. For the most populated states, we identified their potential binding pockets. Then we performed molecular docking of the FDA-approved drugs library, and 15 drugs including reproterol were selected as potential hits inhibiting SRSF6. This work provides valuable insights into the structure and dynamics of SRSF6, which will aid in the structure-based drug design targeting SRSF6 to inhibit tumorigenesis.