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Review
. 2012 Aug;45(3):301-43.
doi: 10.1017/S0033583512000066. Epub 2012 May 9.

Protein flexibility in docking and surface mapping

Katrina W Lexa  1 , Heather A Carlson
Affiliations
Review

Protein flexibility in docking and surface mapping

Katrina W Lexa et al. Q Rev Biophys. 2012 Aug.

Abstract

Structure-based drug design has become an essential tool for rapid lead discovery and optimization. As available structural information has increased, researchers have become increasingly aware of the importance of protein flexibility for accurate description of the native state. Typical protein-ligand docking efforts still rely on a single rigid receptor, which is an incomplete representation of potential binding conformations of the protein. These rigid docking efforts typically show the best performance rates between 50 and 75%, while fully flexible docking methods can enhance pose prediction up to 80-95%. This review examines the current toolbox for flexible protein-ligand docking and receptor surface mapping. Present limitations and possibilities for future development are discussed.

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Figures

Fig. 1
Fig. 1
The conformational variation in holo- and apo structures of beta-secretase 1 illustrates structural differences frequently seen across multiple crystal structures of the same protein.
Fig. 2
Fig. 2
The same protein crystallized with different ligands. This simple two ligand-one protein set demonstrates the influence of structure on the shape of the binding pocket.
Fig. 3
Fig. 3
MUSIC simulations of benzene probes (gray) to the surface of an HIVp monomer (purple). The initial stages are universal to mapping methods, but the combination of the structures in the fourth and final frames are unique to the MPS method. Five hundred probes were flooded onto the protein surface, minimized, and clustered together. Parent probes were identified for each monomer conformation, the HIVp monomers were aligned through a weighted-RMSD function, and then the parent probes were clustered together and retained when at least half of the protein conformations contained a probe at that site. This resulted in low-energy probe clusters (colored red through purple in the final frame) of benzene that could be combined with ethane and methanol clusters to develop a pharmacophore model.
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