Biochemical binding systems present many-body problems, even after integrating over solvent and polymer configurational degrees of freedom, because biological molecules are dense in cellular compartments. Furthermore, the resulting effective potentials are likely to include substantial n-body contributions with n>2. The binding of oxygen to hemoglobin is studied as a prototype problem of this kind. (i) The Hill coefficient (simply related to the change in the fractional binding with a change in the ligand chemical potential) has proven to be a useful, model-independent descriptor of ligand binding behavior. An obvious generalization of this approach is given and the resulting coefficients are shown to describe stably the binding of oxygen to hemoglobin over a broad range of free-ligand concentrations. (ii) An expansion of the standard Helmholtz free energy in the local binding density is used to find the excess standard Helmholtz free energy for saturation of hemoglobin with oxygen. This requires equations to change from local potential field variables to density variables that are equivalent to the two-, three-, and four-point Ornstein-Zernike equations. The method permits exact inclusion of two-, three-, and four-body potentials in the limit of weak interaction potentials, but is very poor for strong interactions. (iii) An expansion of the two-body direct correlation function with r\ensuremath{\ne}0 and the core condition are used in the compressibility equation to find the excess pressure as a function of the fractional saturation, and thus also to find the standard free-energy change upon saturating the protein with ligand.At first order, this procedure provides a model for the binding of oxygen to hemoglobin that does not require the assumption of pair decomposability of the interaction potentials or explicit calculation of a partition function, and yet is competitive with models that require both. The model is accurate for a wide range of interaction potentials. The result is a one-parameter equation of state that does not exhibit a phase transition for a finite system, but may exhibit a phase transition in the limit of infinite system size (depending on the magnitude of the cooperativeness parameter).
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