Is cooperative oxygen binding by hemoglobin really understood?

The enormous success of structural biology challenges the physical scientis t. Can biophysical studies provide a truly deeper understanding of how a pr otein works than can be obtained from static structures and qualitative ana lysis of biochemical data? We address this question in a case study by pres enting the key concepts and experimental results that have led to our curre nt understanding of cooperative oxygen binding by hemoglobin, the paradigm of structure function relations in multisubunit proteins. We conclude that the underlying simplicity of the two-state allosteric mechanism could not h ave been demonstrated without novel physical experiments and a rigorous qua ntitative analysis.