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Protein Eng 1998 Jun;11(6):429-37
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
[Medline record in process]
Although the free energy perturbation approach is a rigorous method for estimating the relative binding free energy between an enzyme and its inhibitors, it is computationally expensive. This paper examines the accuracy at different levels of approximations, following the series expansion of free energy derived by Aqvist et al. Level-0 calculates only the enzyme-inhibitor interaction energy at the minimum energy configuration without solvent. In Level-0MD, the inhibitor configurations are sampled by molecular dynamics. These levels assume that the second- and higher order terms in the series expansion can be neglected and that the interaction energies in the bound and unbound states are equal. Level-1 does not assume equal interaction energies in the bound and unbound states. Level-1S includes the solvent contribution but both enzyme and inhibitor are fixed. In Level-1SMD, the inhibitor configurations are sampled by molecular dynamics. Level-2SMD retains the second-order term. We chose seven HIV-1 protease inhibitors for study: A77003, A76889, A76928, A78791, A74704, JG365 and MVT101. Level-0 and Level-0MD were found to give essentially the same relative interaction energies by using the AMBER force field, suggesting that fixing atomic positions may be a good approximation in some cases. However, as expected, Level-0 or Level-0MD gave poor predictions for the relative binding free energies between hydrophobic inhibitors (e.g. A77003) and more hydrophilic inhibitors (e.g. JG365). Level-1SMD produced a much better correlation between calculated and experimental results. Inclusion of the second-order term did not improve the accuracy.
PMID: 9725621, UI: 98391437
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Biochemistry 1997 Jun 3;36(22):6588-96
Department of Biology and Biocalorimetry Center, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
A structural parametrization of the binding and folding energetics previously developed in this laboratory accounts quantitatively for the binding of 13 HIV-1 protease inhibitors for which high-resolution structures are available (A77003, A78791, A76928, A74704, A76889, VX478, SB203386, SB203238, SB206343, U100313, U89360, A98881, CGP53820). The binding free energies for the inhibitors are predicted with a standard deviation of +/- 1.1 kcal/mol or +/- 10%. Furthermore, the formalism correctly predicts the observed change in inhibition constant for the complex of A77003 and the resistant protease mutant V82A, for which the high-resolution structure is also available. The analysis presented here provides a structural mapping of the different contributions to the binding energetics. Comparison of the binding map with the residue stability map indicates that the binding pocket in the protease molecule has a dual character: half of the binding site is defined by the most stable region of the protein, while the other half is unstructured prior to inhibitor or substrate binding. This characteristic of the binding site accentuates cooperative effects that permit mutations in distal residues to have a significant effect on binding affinity. These results permit an initial assessment of the effects of mutations on the activity of protease inhibitors.
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