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Review
. 2009 Apr 15;17(4):489-98.
doi: 10.1016/j.str.2009.02.010.

Binding of small-molecule ligands to proteins: "what you see" is not always "what you get"

David L Mobley  1 , Ken A Dill
Affiliations
Review

Binding of small-molecule ligands to proteins: "what you see" is not always "what you get"

David L Mobley et al. Structure. .

Abstract

We review insights from computational studies of affinities of ligands binding to proteins. The power of structural biology is in translating knowledge of protein structures into insights about their forces, binding, and mechanisms. However, the complementary power of computer modeling is in showing "the rest of the story" (i.e., how motions and ensembles and alternative conformers and the entropies and forces that cannot be seen in single molecular structures also contribute to binding affinities). Upon binding to a protein, a ligand can bind in multiple orientations; the protein or ligand can be deformed by the binding event; waters, ions, or cofactors can have unexpected involvement; and conformational or solvation entropies can sometimes play large and otherwise unpredictable roles. Computer modeling is helping to elucidate these factors.

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Figures

Figure 1
Figure 1. Relative Publication Numbers for Different Computational Methods
From Google Scholar (July 2008). MM-PBS, molecular-mechanics with Poisson-Boltzmann surface area; RBFE, relative binding free energy; ABFE, absolute binding free energy. Percentages, in the order listed in the legend, are 88%, 1%, 11%, and 0.04%.
Figure 2
Figure 2. Hypothetical Ligand Binding Energy Landscape
Ligand binding energy landscapes (top) can be rough, with multiple minima. These multiple minima can correspond to multiple distinct ligand binding conformations in the receptor (bottom).
Figure 3
Figure 3. Small Changes in a Ligand May Modify the Binding Landscape
It is not uncommon to find that small modifications in a ligand (bottom) may lead to drastic changes in the observed binding mode (bottom) (Stout et al., 1999; Badger et al., 1988; Böhm and Klebe, 1996; Kim, 2007a, 2007b; Pei et al., 2006; Reich et al., 1995; Stoll et al., 2003). This can be explained by an energy landscape with multiple minima (top), which is altered slightly by minor modifications to the ligand (top left versus top right), leading to a substantial change in the binding mode.
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References

    1. Abel R, Young T, Farid R, Berne BJ, Friesner RA. Role of the active-site solvent thermodynamics of factor Xa ligand binding. J Am Chem Soc. 2008;130:2817–2831. - PMC - PubMed
    1. Arora K, Brooks CL., III Large-scale allosteric conformational transitions of adenylate kinase appear to involve a population-shift mechanism. Proc Natl Acad Sci USA. 2007;104:18496–18501. - PMC - PubMed
    1. Babaoglu K, Simeonov A, Irwin JJ, Nelson ME, Feng B, Thomas CJ, Cancian L, Costi MP, Maltby DA, Jadhav A, et al. Comprehensive mechanistic analysis of hits from high-throughput and docking screens against beta-lactamase. J Med Chem. 2008;51:2502–2511. - PMC - PubMed
    1. Badger J, Minor I, Kremer MJ, Oliveira MA, Smith TJ, Griffith JP, Guerin DMA, Krishnaswamy S, Luo M, Rossmann MG, et al. Structural analysis of a series of antiviral agents complexed with human rhino-virus 14. Proc Natl Acad Sci USA. 1988;85:3304–3308. - PMC - PubMed
    1. Barillari C, Taylor J, Viner R, Essex JW. Classification of water molecules in protein binding sites. J Am Chem Soc. 2007;129:2577–2587. - PubMed

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