Interactions between proteins and solvents are important for proteins to maintain their active structures. The structural transition of proteins during their dissolution process in different solvents was investigated. Solvent assisted electric field induced desorption/ionization (SAEFIDI) was used for the investigation. NH4Ac buffers caused significant unfolding of cytochrome c and myoglobin during their dissolution process. Different proteins underwent varied folding and unfolding transitions during dissolution.