S. Vajda et al., EFFECT OF CONFORMATIONAL FLEXIBILITY AND SOLVATION ON RECEPTOR-LIGANDBINDING FREE-ENERGIES, Biochemistry, 33(47), 1994, pp. 13977-13988
A coherent framework is presented for determining the free energy chan
ge accompanying ligand binding to protein receptors. The most importan
t new feature of the method is the contribution of the flexibility of
the free ligand, and hence its conformational change on binding, to th
e free energy. Flexibility introduces two additional terms in the free
energy difference: the internal energy difference between the ligand
in the bound and free states and the backbone entropy loss. The former
requires taking explicit account of the difference in solvation of th
e various forms of the free ligand. The solvation free energy change i
s estimated using an atomic solvation parameter model [Eisenberg and M
clachlan (1986) Nature 319, 199-203], with an improved parameter set.
In order to evaluate the method, we applied it to three data sets for
which increasingly general methods are required. The set to which the
most restrictive theory can be applied consists of eight crystallized
enpopeptidase-protein inhibitor complexes which do not change conforma
tion on binding and for which the major contribution to the solvation
free energy is entropic. The results are in good agreement with the me
asured values, and somewhat better than those previously reported in t
he literature. The second data set compares the relative binding free
energies of biotin and its analogs for streptavidin. In this case the
structures are also rigid, but solvation free energy must include both
enthalpic and entropic components. We find that differential free ene
rgy predictions are approximately the same as those obtained by free e
nergy perturbation techniques. The final application is an analysis of
the measured stabilities of 13 different MHC receptor-peptide complex
es. In this case we show that flexibility contributes 30-50% of the fr
ee energy change and find a correlation of 0.88 between our predicted
free energies and peptide dissociation times.