We present an extended MM3 model for catecholamide ligands and their Fe3+ complexes and the application of this model to understand how ligand architecture effects Fe3+ binding affinity. Force field parameters were fit to geometries and energies from electronic structure calculations, and to crystal structure data. Optimized geometries are reported for phenol, acetamide, the phenol-phenol dimer, the acetamide -phenol dimer, and N-methylsalicylamide (HMSA) at the BLYP/DZVP2/A2 level of theory. Optimized geometries and relative energies are reported for the pseudo-octahedral ground state and the trigonal planar transition state of [Fe(CAT)(3)](3-) at the VWN/.DZVP2/Al level of theory. The MM3 model is validated by comparison of calculated structures with crystal structures containing 1,2-dihydroxybenzene (H(2)CAT) and 2,3-dihydroxy-N-methylbenzamide (H(2)MBA) fragments, crystal structures of [Fe(CAT)(3)](3-) and tris-catecholamide Fe3+ complexes, and comparison of MM3 (6.8 kcal/ mol) and VWN (5.9 kcal/mol) barriers for intramolecular octahedral inversion in [Fe(CAT)(3)](3-). The MM3 model also rationalizes the higher inversion barrier (14 to 18 kcal/mol) reported for [Ga(NN-diisopropylterephthalamide)(3)](3)([Ga(DIPTA)(3)](3-)). Conformational searches were performed on enterobactin (H6ENT), 1,3,5-tris(2,3-dihydroxy-benzamidomethyl)-2,4,6-triethylbenzene (H(6)EMECAM), 1,3,5-tris(2,3-dihydroxybenzamidomethyl)-2,4,6-trimethylbenzene (H(6)MMECAM), 1,3,5-tris(2,3-dihydroxybenzamidomethyl)benzene (H(6)MECAM), and 1,5,9-N,N',N'-tris(2,3-dihydroxybenzoyl)cyclotriazatridecane (H-6-3,3,4-CYCAM) and Fe3+ complexes with each of these ligands. A conformational search also was done on the Fe3+ complex with the 2,2',2"-tris(2,3-dihydroxybenzamido)triethylammonium cation (H(7)TRENCAM(+)). The relationship between calculated steric energies and measured thermodynamic quantities is discussed, and linear correlations between formation constants and steric energy differences are reported. Extrapolation to zero strain predicts formation constants 8 +/- 5 orders of magnitude higher than that exhibited by ENT (10(49)) are possible. This prediction is supported by a formation constant of 10(63) estimated from the formation constant of [Fe(2,3-dihydroxy-N,N-dimethylbenzamide)(3)](3-) ([Fe(DMBA)(3)](3-)) by considering the entropic consequences of connecting three DMBA ligands to a rigid backbone. Structural criteria for the identification of improved tris-catecholate ligand architectures are presented.