|
Examples of Employing the Residual Potential
As an example of determining electrostatic complementarity through
the examination of electrostatic potentials at the surface of molecules,
here we examine the binding of the ligand barstar to the small bacterial
ribonuclease from Bacillus amyloliquefaciens, barnase [1,2].
First, we examine the binding process using the standard method used
by structural biophysicists. In this method, protein complementarity is
determined by coloring the surface of the receptor and ligand based upon
the respective total solvent-screened electrostatic potential of these
molecules in the unbound state. Then, one looks for regions where the
colors are opposite (for complementarity) or the same (for electrostatic
clashes). For simplicity of comparison, instead of displaying these
potentials on the different surfaces of each molecule, the receptor's
(barnase's) potential was projected onto the ligand's (barstar's) surface.
The scale on all the following figures is (-15,0,30) for barnase's
potential in GRASP notation and units of kT/e, where negative values are
red and positive values are blue. For barstar and the complementary
ligand the scale is (-30,0,15).
Figure 1: Unbound electrostatic potentials as inaccurate
determinants of complementarity.
|
|
Barnase potential projected onto barstar |
Barstar |
Comparison of barnase and barstar indicates some regions that seem
complementary and some regions that do not. The shortcoming
of examining unbound potentials such as these is that they do not take
into account the important free energy cost incurred through desolvation
upon binding, and thus give an incomplete picture of the energetics
involved. Furthermore, there is no meaningful comparison of these ligand
and receptor surface potentials that gives a true indication of their
complementarity in terms of the binding free energy.
If, instead of examining the electrostatic potentials in the
unbound state, one compares the two
components of the Residual potential, one does have a quantitative
measure. For a complementary ligand, these two components must be equal
in magnitude and opposite in value all over the ligand surface. For
non-complementary ligands, the equivalence will not hold and differences
in the potentials reflect regions of non-complementarity within the ligand
[3].
The scales for the figures below are double those from above.
Figure 2: Components of the Residual potential determines
complementarity.
|
|
Barnase bound-state potential (Interaction potential) projected onto barstar |
Barstar desolvation potential |
|
|
|
Complementary ligand desolvation potential |
From these images, one can once again see that barnase and barstar
are fairly complementary; in fact, they seem much more complementary than
indicated by Figure 1, differing on this scale at only a few places.
Comparison, of the complementary ligand to barnase, reveals that the
potential maps match almost exactly (the optimization procedure could be
further refined with increased computational effort for a better match, but
little additional binding free energy would result [2,3]). The Residual
potential does indeed indicate complementarity.
These images were obtained using the
GRASP computer program [4].
Scripts to automate obtaining similar images for other molecules along
with instructions for using them are given in the next page, Software.
References
[1] Computation of Electrostatic Complements to Proteins: A Case of Charge Stabilized Binding.
L. T. Chong, S. E. Dempster, Z. S. Hendsch, L.-P. Lee, and B. Tidor.
Protein Sci.
7: 206-210 (1998).
[2] Optimization of Binding Electrostatics: Charge Complementarity in the Barnase-Barstar Protein Complex.
L.-P. Lee and B. Tidor.
Protein Sci.
10: 362-377 (2001).
[3] Optimizing Electrostatic Affinity in Ligand-Receptor Binding: Theory, Computation, and Ligand Properties.
E. Kangas and B. Tidor.
J. Chem. Phys.
109: 7522-7545 (1998).
[4] Protein Folding and Association: Insights From the Interfacial and Thermodynamic Properties of Hydrocarbons.
A. Nicholls, K. A. Sharp, and B. Honig.
Proteins: Struct., Funct., Genet.
11: 281-296 (1991).
Accessibility
|
|