This proposal outlines the application of in-solution synchrotron SAXS to investigate HSPB8, an intrinsically disordered protein acting as a chaperone in protein folding and aggregation prevention. The primary objective is to elucidate the biophysical changes induced by the pathogenic mutant K141E on the stability and function of HSPB8. SAXS experiments will be conducted under different conditions for both the wild type and the pathogenic mutant, including temperature, ionic strength, and concentration of paroxetine, an antidepressant drug. The collected SAXS data will be analyzed with the variational Bayesian method (VBWSAS) aimed to re-weight the ensemble of conformers derived from enhanced sampling atomistic simulations. The integration of SAXS data with computational simulations will provide a comprehensive understanding of the structural alterations associated with HSPB8 mutations and the effect of drugs shown to restore the chaperone activity of the mutant protein.