Calculation of the relative change in binding free energy of a protein-inhibitor complex

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Science  30 Jan 1987:
Vol. 235, Issue 4788, pp. 574-576
DOI: 10.1126/science.3810157


By means of a thermodynamic perturbation method implemented with molecular dynamics, the relative free energy of binding was calculated for the enzyme thermolysin complexed with a pair of phosphonamidate and phosphonate ester inhibitors. The calculated difference in free energy of binding was 4.21 +/- 0.54 kilocalories per mole. This compares well with the experimental value of 4.1 kilocalories per mole. The method is general and can be used to determine a change or "mutation" in any system that can be suitably represented. It is likely to prove useful for protein and drug design.

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