Molecular Mechanics Studies of Model Iron(III) Transferrin Complexes in Vacuo and in Aqueous Solution

A molecular mechanics (MM) investigation of low-molecular-weight ferric chelates has been conducted to develop iron parameters appropriate to the AMBER all-atom force field for subsequent MM studies of ferric transferrin. These force-field parameters were derived (1) by fitting of the crystal structure geometries of the Fe(III) complexes of ethylenebis(o-hydroxyphenylglycine) (EHPG), 1,4,7-triazacyclononane-1,4,7-triacetic acid (TCTA), and 1,5-diazapentane-1,1,5,5-tetraacetic acid (TRDTA), (2) by conducting a statistical analysis of 44 crystal-structure geometries of Fe(III) complexes extracted from the Cambridge Structural Database, and (3) by making comparisons with published force-field parameters relevant to transition metal complexes. Energy minimized molecular structures and conformational energies of the (R,R), (R,S), and (S,S) isomers of EHPG were calculated both in vacuo and in aqueous solution estimated (1) crudely using a distance-dependent dielectric constant ε and (2) more rigorously using the generalized Born/surface area (GB/SA) continuum treatment of Still. Rms deviations between the present GB/SA-calculated and published crystal-structure geometries for the R,R rac isomer of Fe^IIIEHPG are 0.044 Å for bond lengths, 3.15° for bond angles, and 6.9° for torsion angles. The corresponding rms deviations for the R,S meso isomer are 0.025 Å for bond lengths, 2.78° for bond angles, and 5.5° for torsion angles. Similar rms deviations were obtained for the Fe^IIITCTA, Fe^IIITRDTA, and Fe^IIIEDDDA [(ethylenediamine-N,N´-diaceto-N,N´-di-3-propionato)iron(III)] complexes. The calculated conformational energies for the Fe^IIIEHPG complexes show that (1) the order of increasing stability is S,S rac < R,S meso < R,R rac, (2) this order does not change whether calculated in vacuo or in aqueous solution, and (3) aqueous solvation reduces the energy differences among the three conformers. The GB/SA-calculated energy difference of 2.89 kcal/mol between the R,R rac and R,S meso conformers compares well with experimentally measured stability constants corresponding to Δ(ΔG) of 1.65 and 3.10 kcal/mol. The failure to observe the S,S rac conformer in the crystal is attributed to its inherent instability rather than to unfavorable crystal packing. The calculated order of stability for the three Fe^IIIEDDDA conformers was trans-(O₆,) <trans-(O₅,O₆) < trans-(O₅), of which the trans-(O₅) conformer is the only form observed in the crystal. The present MM calculations predict that optimum stability is achieved when the ligands adopt an equitorial coordination plane containing a 6, 5,6 combination of chelate-ring sizes, with two 5-membered axial chelate rings.