The insulin receptor (IR) is a homo-dimeric, disulfide-linked, membrane-spanning tyrosine kinase. IR displays negative cooperativity in insulin binding to its two pockets, suggesting "see-sawing" between symmetry-inverted conformations. The crystal structure of the dimeric IR ectodomain, IRDeltabeta [PDB code 2DTG (McKern et al., Nature 2006 443:218-221)], provides structural bases for this speculation. Unfortunately, neither binding pocket of the crystallographic IRDeltabeta structure allows steric accommodation of insulin. During almost 70-ns of all-atom, explicit-water MD simulation ( approximately 0.5 million atoms), IRDeltabeta undergoes significant asymmetric interdomain and intersubunit conformational fluctuations that do not alter its quaternary structure. Subtle variations in intersubunit buried surface area coincide with these conformational fluctuations, resulting in one easily-accessible insulin binding pocket with the other blocked. We use a combination of Metropolis Monte-Carlo and MD simulations to dock both T- and R-state insulin into the open binding pocket. Both complexes remain stable during 30-ns of MD simulation. In these complexes, "hexamer interface" residues on insulin directly contact the "site-2" epitope on the first type-III fibronectin domain (F1) of IR. Our results support the hypothesis that intersubunit flexibility of IR, governed by alternating modulation of buried intersubunit surface area, is the physical mechanism underlying a "see-saw" model of negative cooperativity.