In order to compare the free energy landscapes for DFO and 4HMS, we repeated our umbrella sampling simulations of 4HMS, using again the CN as a collective variable. The harmonic constant chosen was k = 20k B T with the centers of the constraints going from CN = 2 to CN = 8 using a 0.5 step. The total accumulated length of these MD simulations was 11µsec. Fig. compares the FES of the Zr 4+ -DFO complex (left panel) with that for Zr 4+ -4HMS (right panel). The FES for the two systems are strikingly different and confirm the experimental observations of the greater efficacy of 4HMS as a chelator compared to DFO. Specifically, the free energy minimum of 4HMS corresponds to a structure where all the four hydroxamate groups envelop the Zr 4+ . For example, configurations at CN ≃ 3.5, which is the most stable value for DFO, are now ≃ 35k B T higher in free energy than the global minimum in 4HMS. Thus, in sharp contrast to what is observed for DFO, higher CN are more favored than lower ones fully consistent with the experimental observations. 1