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Calculation of ligand binding free energies from molecular dynamics simulations

✍ Scribed by J. Marelius; T. Hansson; J. Åqvist

Publisher
John Wiley and Sons
Year
1998
Tongue
English
Weight
247 KB
Volume
69
Category
Article
ISSN
0020-7608

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✦ Synopsis

A recently developed method for predicting binding affinities in ligand᎐receptor complexes, based on interaction energy averaging and conformational sampling by molecular dynamics simulation, is presented. Polar and nonpolar contributions to the binding free energy are approximated by a linear scaling of the corresponding terms in the average intermolecular interaction energy for the bound and free states of the ligand. While the method originally assumed the validity of electrostatic linear response, we show that incorporation of systematic deviations from linear response derived from free energy perturbation calculations enhances the accuracy of the approach. The method is applied to complexes of wild-type and mutant human dihydrofolate reductases with 2,4-diaminopteridine and 2,4-diaminoquinazoline inhibitors. It is shown that a binding energy accuracy of about 1 kcalrmol is attainable even for multiply ionized compounds, such as methotrexate, for which electrostatic interactions energies are very large.

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