SPDP-type reagents have an amine-reactive N-hydroxysuccinimide (NHS) ester at one end and a suflhydryl-reactive 2-pyridyldithiol group at the opposite end. PEG4-SPDP has a 4-unit polyethylene glycol spacer arm, which confers greater solubility to the crosslinker and linked proteins compared to crosslinkers having only hydrocarbon spacers. Pyridyldithiol reagents produce disulfide-containing linkages that can be cleaved with reducing agents such as dithiothreitol (DTT). Crosslinking experiments with SPDP reagents are not limited to those involving proteins. Any of a variety of molecules with primary amines and sulfhydryl groups can be modified or crosslinked using an SPDP reagent.