The eight ligands whose binding with FKBP was considered. Their free energies of binding were all experimentally measured by Holt et al., and the naming follows that work. L20 is FK506, a naturally occurring inhibitor of FKBP that is utilized pharmaceutically.
The computed free energies of (a) complex decoupling and (b) desolvation for each ligand. The range of the minimum to maximum free energy observed for any configurational state, , is shown. The horizontal bars denote the final POPFEP outputs.
Computed binding free energies using POPFEP vs experimentally measured binding free energies for eight FKBP ligands. The lines and are drawn as guides. The most outlying point is associated with L12.
Treating each set of simulations we had begun from a given conformation independently, the minimum to maximum decoupling energies observed. The horizontal bars denote the decoupling free energies obtained from using the starting conformations of Ref. 10.
Solvation free energies computed using data from between time points of 30 and of the FEP trajectories and using data between time points of and (error bars too small to be seen). The line is drawn as a guide. The outlier is L5.
Free energy of decoupling the ligand within the binding pocket (including volume correction), as computed using data between time points 30 and of trajectories or using data between 30 and of trajectories. All ligands show agreement within error except for L9.
The binding free energies obtained from experimental values and the computed free energies. All values are in kcal/mol.
The ligand solvation, complex coupling, and overall binding free energies reported in Ref. 10. The RMSDs of the solvation, complex coupling, and binding free energy column with the corresponding columns in Table I are 1.9, 4.0, and , respectively. We emphasize that direct comparison of complex coupling or binding energies is complicated by the fact that the protocol of Ref. 10 did not make connection with the standard state volume.
Complex decoupling energies obtained using only simulations from an initial complex obtained through lengthy structural equilibration (structures from Ref. 10) and the decoupling energies obtained using Eq. (10) with simulations began at multiple structures. (All using data between the 30 and point of trajectories.) All values are in kcal/mol. the RMSD between the two columns is .
Ligand solvation energies and complex coupling energies (plus volume correction) obtained from longer simulation. Data from of each trajectory was used for the ligands and from for the complexes. All values are in kcal/mol. The same data is presented in Figs. 5 and 6 in comparison to the results using less data.
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