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The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities.

Genheden S, Ryde U - Expert Opin Drug Discov (2015)

Bottom Line: MM/PBSA and MM/GBSA are attractive approaches owing to their modular nature and that they do not require calculations on a training set.They have been used successfully to reproduce and rationalize experimental findings and to improve the results of virtual screening and docking.However, they contain several crude and questionable approximations, for example, the lack of conformational entropy and information about the number and free energy of water molecules in the binding site.

View Article: PubMed Central - PubMed

Affiliation: University of Southampton, School of Chemistry , Highfield, SO17 1BJ, Southampton , UK.

ABSTRACT

Introduction: The molecular mechanics energies combined with the Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches to estimate the free energy of the binding of small ligands to biological macromolecules. They are typically based on molecular dynamics simulations of the receptor-ligand complex and are therefore intermediate in both accuracy and computational effort between empirical scoring and strict alchemical perturbation methods. They have been applied to a large number of systems with varying success.

Areas covered: The authors review the use of MM/PBSA and MM/GBSA methods to calculate ligand-binding affinities, with an emphasis on calibration, testing and validation, as well as attempts to improve the methods, rather than on specific applications.

Expert opinion: MM/PBSA and MM/GBSA are attractive approaches owing to their modular nature and that they do not require calculations on a training set. They have been used successfully to reproduce and rationalize experimental findings and to improve the results of virtual screening and docking. However, they contain several crude and questionable approximations, for example, the lack of conformational entropy and information about the number and free energy of water molecules in the binding site. Moreover, there are many variants of the method and their performance varies strongly with the tested system. Likewise, most attempts to ameliorate the methods with more accurate approaches, for example, quantum-mechanical calculations, polarizable force fields or improved solvation have deteriorated the results.

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Related in: MedlinePlus

The number of hits per year in Web of Science when searching for the topics MM/PBSA, MM-PBSA, MM/GBSA or MM-GBSA.
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Figure 0001: The number of hits per year in Web of Science when searching for the topics MM/PBSA, MM-PBSA, MM/GBSA or MM-GBSA.

Mentions: This method was developed by Kollman et al. in the late 90s [8] and has enjoyed a high popularity ever since, with 100 – 200 publications each of the latest 5 years, as can be seen in Figure 1. The method has been used in a range of settings, including protein design [9], protein–protein interactions [10,11], conformer stability [12,13] and re-scoring [14,15]. In this paper, we present a critical review of the method and its ability to predict ligand-binding affinities. In particular, we discuss the precision and accuracy of the results and whether it is possible to improve the method by using more accurate approaches for each of the terms in the method, whereas specific applications are better covered in previous reviews [7,16-18]. Several methods with similarity to MM/PBSA have been suggested both earlier and later [19-21], but none of them has found any wide application.


The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities.

Genheden S, Ryde U - Expert Opin Drug Discov (2015)

The number of hits per year in Web of Science when searching for the topics MM/PBSA, MM-PBSA, MM/GBSA or MM-GBSA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487606&req=5

Figure 0001: The number of hits per year in Web of Science when searching for the topics MM/PBSA, MM-PBSA, MM/GBSA or MM-GBSA.
Mentions: This method was developed by Kollman et al. in the late 90s [8] and has enjoyed a high popularity ever since, with 100 – 200 publications each of the latest 5 years, as can be seen in Figure 1. The method has been used in a range of settings, including protein design [9], protein–protein interactions [10,11], conformer stability [12,13] and re-scoring [14,15]. In this paper, we present a critical review of the method and its ability to predict ligand-binding affinities. In particular, we discuss the precision and accuracy of the results and whether it is possible to improve the method by using more accurate approaches for each of the terms in the method, whereas specific applications are better covered in previous reviews [7,16-18]. Several methods with similarity to MM/PBSA have been suggested both earlier and later [19-21], but none of them has found any wide application.

Bottom Line: MM/PBSA and MM/GBSA are attractive approaches owing to their modular nature and that they do not require calculations on a training set.They have been used successfully to reproduce and rationalize experimental findings and to improve the results of virtual screening and docking.However, they contain several crude and questionable approximations, for example, the lack of conformational entropy and information about the number and free energy of water molecules in the binding site.

View Article: PubMed Central - PubMed

Affiliation: University of Southampton, School of Chemistry , Highfield, SO17 1BJ, Southampton , UK.

ABSTRACT

Introduction: The molecular mechanics energies combined with the Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches to estimate the free energy of the binding of small ligands to biological macromolecules. They are typically based on molecular dynamics simulations of the receptor-ligand complex and are therefore intermediate in both accuracy and computational effort between empirical scoring and strict alchemical perturbation methods. They have been applied to a large number of systems with varying success.

Areas covered: The authors review the use of MM/PBSA and MM/GBSA methods to calculate ligand-binding affinities, with an emphasis on calibration, testing and validation, as well as attempts to improve the methods, rather than on specific applications.

Expert opinion: MM/PBSA and MM/GBSA are attractive approaches owing to their modular nature and that they do not require calculations on a training set. They have been used successfully to reproduce and rationalize experimental findings and to improve the results of virtual screening and docking. However, they contain several crude and questionable approximations, for example, the lack of conformational entropy and information about the number and free energy of water molecules in the binding site. Moreover, there are many variants of the method and their performance varies strongly with the tested system. Likewise, most attempts to ameliorate the methods with more accurate approaches, for example, quantum-mechanical calculations, polarizable force fields or improved solvation have deteriorated the results.

Show MeSH
Related in: MedlinePlus