Intrinsically disordered protein (IDP) plays an important role in liquid-liquid phase separation (LLPS). RNA-binding protein fused in sarcoma (FUS) is a well-studied IDP that induces LLPS since its low-complexity core region (FUS-LC-core) is essential for droplet formation through contacts between FUS-LC-cores. Several experimental studies have reported that adenosine triphosphate (ATP) concentrations modulate LLPS-driven droplet formation through the dissolution of FUS. To elucidate the role of ATP in this dissolution, microsecond-order all-atom molecular dynamics (MD) simulations were performed for a crowded system of FUS-LC-cores in the presence of multiple ATP molecules. Our analysis revealed that the adenine group of ATP frequently contacted the FUS-LC-core, and the phosphoric acid group of ATP was exposed to the external solvent, which promoted both hydration and solubilization of FUS.

Parallel cascade selection molecular dynamics (PaCS-MD) is a rare-event sampling method that generates transition pathways between a reactant and product. To sample the transition pathways, PaCS-MD repeats short-time MD simulations from important configurations as conformational resampling cycles. In this study, PaCS-MD was extended to sample ligand binding pathways toward a target protein, which is referred to as LB-PaCS-MD. In a ligand-concentrated environment, where multiple ligand copies are randomly arranged around the target protein, LB-PaCS-MD allows for the frequent sampling of ligand binding pathways. To select the important configurations, we specified the center of mass (COM) distance between each ligand and the relevant binding site of the target protein, where snapshots generated by the short-time MD simulations were ranked by their COM distance values. From each cycle, snapshots with smaller COM distance values were selected as the important configurations to be resampled using the short-time MD simulations. By repeating conformational resampling cycles, the COM distance values gradually decreased and converged to constants, meaning that a set of ligand binding pathways toward the target protein was sampled by LB-PaCS-MD. To demonstrate relative efficiency, LB-PaCS-MD was applied to several proteins, and their ligand binding pathways were sampled more frequently than conventional MD simulations.

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The heterodimer (T1r2a LBD and T1r3 LBD) of medaka fish taste receptor type 1 provides multiple binding modes, which may be helpful in discriminating various taste substances or detecting concentrations of nutrients efficiently.