Free-energy perturbation , complex

The Free Energy Perturbation method provides the most accurate values of energy differences by simulations [37]. However, to our knowledge this method was only once applied to CD complexes [38], but too little information about the procedure applied, provided in this paper, precludes the assessment of its reliability. 

For the three conformers, the binding sequence is Na > K > Rb > Cs. This is supported by energy component analysis on the trajectories, as well as by Free energy perturbation (FEP) calculations. Intrinsically, Cs+ has the weakest interactions with both hosts. The largest contribution of the cation/host interaction energy comes from the ether ring rather than from the aromatic moieties. Each complex displays a clear conformational preference. Sodium is most stable in the cone conformation, whereas cesium is most stable in the 1,3-altemate conformation. 

Fig. 2 Free energy perturbation (FEP) diagram, showing drugs D and D binding to receptor R to give the DR and DR receptor complex and the free energy changes.

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