The six ligands of FKBP sorted according to binding affinity.

The six ligands are: BUT, 4-hydroxy-2-butanone; DMSO, dimethylsulfoxide;
DAP, 5-diethylamino-2-pentanone; DSS, methyl sulphinyl-methyl
sulphoxide; PENT, 5-hydroxy-2-pentanone; THI, tetrahydrothiophene
1-oxide.
aAn unbinding event is defined as a separation of the ligand center of
mass from the center of the FKBP binding site larger than 15
Å.
bA rebinding event is defined as an unbinding event followed by a
separation of the ligand/FKBP binding site smaller than 10 Å.
cThe binding affinity in the LIE model is approximated as the difference
of the interaction energy of the ligand with two different surroundings,
the protein and solvent in the bound state and only the solvent in the
unbound state [50]. The LIE binding energy is calculated by
averaging separately over all bound or unbound conformations using a
cutoff of the intermolecular distance of 15 Å to discriminate
between bound and unbound. The electrostatic energy term is multiplied
by 0.5 to be consistent with the hydration energy of a single ion, which
is equal to half the corresponding ion-water interaction energy [54]. The
van der Waals energy term is multiplied by an empirical parameter 0.56
which is derived from linear fitting using only the five neutral
compounds. Each of the total sampling is divided into five blocks and
the block averaging errors for both energy terms are given in the
table.
dThe unbinding time is
calculated by a single exponential fit of the cumulative distribution of
the unbinding events detected along the MD trajectories (see Fig. 5). The unbinding
time and error for each ligand are evaluated by single-exponential
fitting using 25 randomly selected MD runs out of 50, and calculating
the average error for the remaining 25 MD runs not used for the fitting,
i.e., the difference between the value predicted by the fitting curve
and the unbinding time measured along the MD trajectory. This procedure
is repeated 100 times for each ligand, and average values of unbinding
time and cross-validated error are reported in the table.
eMeasured by a fluorescence assay [30].