Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 May;10(5):449-61.
doi: 10.1517/17460441.2015.1032936. Epub 2015 Apr 2.

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

Samuel Genheden  1 , Ulf Ryde
Affiliations
Review

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

Samuel Genheden et al. Expert Opin Drug Discov. 2015 May.

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.

Keywords: drug design; electrostatics; entropy; free energy perturbation; linear interaction energy; non-polar solvation; solvation.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
The number of hits per year in Web of Science when searching for the topics MM/PBSA, MM-PBSA, MM/GBSA or MM-GBSA.
Figure 2.
Figure 2.
Dependence of the MM/PBSA results on the continuum-solvation model for the binding of seven biotin analogues to avidin.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gohlke H, Klebe G. Approaches to the description and prediction of the binding affinity of small-molecule ligands to macromolecular receptors. Ang Chem Int Ed. 2002;41:2644–76. - PubMed

    2. Good review on computational approaches to ligand binding.

    1. Shirts MR, Mobley DL, Chodera JD. Alchemical free energy calculations: ready for prime time? Ann Rep Comput Chem. 2007;3:41–59.
    1. Homeyer N, Stoll F, Hillisch A, et al. Binding free energy calculations for lead optimization: assessment of their accuracy in an industrial drug design context. J Chem Theory Comput. 2014;10:3331–44. - PubMed
    1. Sham YY, Chu ZT, Tao H, et al. Examining methods for calculations of binding free energies: LRA, LIE, PDLD-LRA, and PDLD/S-LRA calculations of ligands binding to an HIV protease. Proteins. 2000;39:393–407. - PubMed
    1. Åqvist J, Medina C, Samuelsson JE. A new method for predicting binding affinity in computer-aided drug design. Proteins Eng. 1994;7:385–91. - PubMed

Publication types