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An improved method to predict the entropy term with the MM/PBSA approach

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Abstract

A method is suggested to calculate improved entropies within the MM/PBSA approach (molecular mechanics combined with Poisson–Boltzmann and surface area calculations) to estimate protein–ligand binding affinities. In the conventional approach, the protein is truncated outside ~8 Å from the ligand. This system is freely minimised using a distance-dependent dielectric constant (to simulate the removed protein and solvent). However, this can lead to extensive changes in the molecular geometry, giving rise to a large standard deviation in this term. In our new approach, we introduce a buffer region ~4 Å outside the truncated protein (including solvent molecules) and keep it fixed during the minimisation. Thereby, we reduce the standard deviation by a factor of 2–4, ensuring that the entropy term no longer limits the precision of the MM/PBSA predictions. The new method is tested for the binding of seven biotin analogues to avidin, eight amidinobenzyl-indole-carboxamide inhibitors to factor Xa, and two substrates to cytochrome P450 3A4 and 2C9. It is shown that it gives more stable results and often improved predictions of the relative binding affinities.

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Acknowledgements

This investigation has been supported by grants from the Swedish research council and the Villum Kann Rasmussen foundation (Denmark), and by computer resources of Lunarc at Lund University.

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  1. Department of Theoretical Chemistry, Lund University, Chemical Centre, P. O. Box 124, SE-221 00, Lund, Sweden

    Jacob Kongsted & Ulf Ryde

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  1. Jacob Kongsted
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Correspondence to Ulf Ryde.

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Kongsted, J., Ryde, U. An improved method to predict the entropy term with the MM/PBSA approach. J Comput Aided Mol Des 23, 63–71 (2009). https://doi.org/10.1007/s10822-008-9238-z

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