A family oftotally synthetic models for the carbon Rt monoxide adducts of heme proteins has been synthesized and ap-R2/ plied to the elucidation of the role of steric (13,14). It has been proposed that the crowding is responsible for the partial detoxification ofcarbon monoxide in respiring organisms (4, 11). For example, the ratio of equilibrium constants (12-18) for CO and 02 binding (formation) Kco/Ko2 for a protein-free modified heme having no structural counterpart to the distal imidazole (Traylor's chelated protoheme) is 840, whereas the corresponding ratio in myoglobin under comparable conditions is 20 (15). The discrimination against carbon monoxide by myoglobin is evident from the fact that the equilibrium constant for 02 binding for the chelated protoheme (2.0 x 106 M-1) is very close to the value for myoglobin (1.5 x 106 M-1). The behavior ofa model having an anthracene suspended above a porphyrin has given support to the conclusion that steric effects can weaken CO binding to heme iron (13). Studies on the equilibrium constants for CO and NO binding, both to model compounds and to heme proteins, confirm the role of a steric effect in weakening the binding of CO to myoglobin (19). In contrast, there is no substantial selective process, steric or otherwise, operating against the binding to iron of CO, as compared to 02, in the case of Hb(R) (12). These results generate two related questions, because the FeCO linkage is distorted (1-3) in both crystalline Hb(R)(CO) and crystalline Mb(CO): (i) Do steric effects that push the normally linear FeCO group into some off-axis configuration necessarily decrease the CO affinities of iron(II) complexes? (ii) If yes, are there structural differences between the carbon monoxide complex of Hb(R)(CO) in aqueous solutions or suspension (20) and in its crystalline state that would account for the apparent contradiction?The structural origins of modifications in 02 affinity are well illustrated by the T and R forms ofhemoglobin. For 02 binding, the equilibrium constant is altered by changes in the rate of dissociation and is attributable to constraints placed on the proximal imidazole by protein conformation and the ease with which the iron atom may occupy the N4 plane of the protoporphyrin (4-11, 21).We report here a systematic and definitive demonstration that steric effects can indeed control the CO affinity of iron(II). This is shown by direct equilibrium measurements with a family ofnonporphyrin heme protein models coupled with key crystal structure analyses. The ligands in our models contain superstructure components that facilitate control of the space available for the binding of CO to an iron(II) atom (22). These socalled lacunar ligands are neutral, bicyclic molecules having conformations that incorporate permanent voids in the vicinity of a metal coordination site (see Fig. 1). The efficacy of these synthetic species as biological mimics has been shown through studies on the reversibly formed 1:1 oxygen adducts of the cobalt(II) and iron(II) compl...

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