- Oral presentation
- Open Access
Variation of geometrical and physicochemical properties in protein binding pockets and their ligands
BMC Bioinformatics volume 8, Article number: S1 (2007)
Physicochemical complementarity is commonly believed to be the driving force for molecular binding. The complementarity for example of electrostatic potentials is regarded as the force that draws the ligand from the solvent into the binding site . If this hypothesis is true, the same ligand should encounter complementarity environmental properties in all proteins to which it binds. We have used our recently published ligand and binding pocket matching algorithm  to test this common assumption by searching for property distributions that are similar for the same ligand bound to different proteins.
The algorithm bases on real spherical harmonic functions, which are applicable to approximate any property function on a unit sphere. These property functions can either be of geometrical or physicochemical nature. For our current analysis we used the shape of binding pockets to test their geometrical similarity and mapped electrostatic, van der Waals and hydrophobicity potentials of the protein on the ligand surface to simulate the physicochemical forces that a ligand may feel in its binding site.
It was discovered that, of these properties the two that vary least for a given ligand are the binding conformation of the ligand followed by the shape of the binding pocket. Conversely, the same ligand encountered very different electrostatic and van der Waals potential environments in the different proteins to which it is bound. These properties were often found not to be complementary to the ligand's properties, which is in conflict with the general assumption stated above. However, the hydrophobicity of the binding pocket did seem to correlate with the properties of the ligand bound to the protein. Hydrophobic parts of the ligand are often confronted with hydrophobic parts of the protein, giving rise to similar hydrophobicity distributions within different binding pockets binding the same ligand (see Figure 1).
These results demonstrate that binding sites that bind the same ligand can exhibit a large variation of properties by facing different physicochemical forces within different binding sites. The results urge a re-evaluation of the total contribution of some physicochemical properties to molecular recognition and the factors that drive molecular binding.
Livesay DR, Jambeck P, Rojnuckarin A, Subramaniam S: Conservation of electrostatic properties within enzyme families and superfamilies. Biochemistry 2003, 42(12):3464–3473. 10.1021/bi026918f
Kahraman A, Morris RJ, Laskowski RA, Thornton JM: Shape variation in protein binding pockets and their ligands. J Mol Biol 2007, 368: 283–301. 10.1016/j.jmb.2007.01.086
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res 2000, 28: 235–242. 10.1093/nar/28.1.235
Conti E, Stachelhaus T, Marahiel MA, Brick P: Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S. Embo J 1997, 16: 4174–4183. 10.1093/emboj/16.14.4174
The molecules in the figure were rendered using PyMOL (W.L. DeLano, http://pymol.sourceforge.net/).
About this article
Cite this article
Kahraman, A., Morris, R.J., Laskowski, R.A. et al. Variation of geometrical and physicochemical properties in protein binding pockets and their ligands. BMC Bioinformatics 8, S1 (2007). https://doi.org/10.1186/1471-2105-8-S8-S1
- Harmonic Function
- Electrostatic Potential
- Binding Pocket
- Match Algorithm
- Molecular Recognition