Additivity and the physical basis of

Christensen T., Gooden D. M., Kung J. E., and Toone E. J. (2003) Additivity and the physical basis of
multivalency effects: a thermodynamic investigation of the calcium EDTA interaction. J Am Chem Soc
125, 7357-7366.
Abstract: To better understand the origin of multivalency effects in ligand binding, the binding of a series
of mono-, bi-, tri- and tetravalent carboxylate ligands to Ca(II) was examined by isothermal titration
calorimetry (ITC). The data are inconsistent with an entropic origin of enhanced affinity, but rather show
that at least in this instance the multivalency effect is enthalpic in origin. Analysis of binding data using the
Jencks model shows the addition of incremental carboxylate "ligands" produces an unfavorable interaction
entropy that is more than offset by a strongly favorable interaction enthalpy. The most likely source of this
interaction enthalpy is the relief of repulsive Coulombic interactions in the unbound state. The
conformational entropy penalty arising from the restriction of flexible dihedrals is negligible, within
experimental error. On the other hand, an enthalpic contribution from linker restriction contributes strongly
to the overall thermodynamics of ligand binding. Together, these data suggest that enthalpic effects
dominate ligand binding, and design strategies 首ld seek to optimize these interactions. The
incorporation of unfavorable interactions in the unbound ligand that are relieved during binding provides an
important mechanism by which to enhance ligand affinities. 等温滴定微量热仪(生物大分子相互作用仪) ITC ,MicroCal