Most of the publications which show a molecular docking model focus mainly on hydrogen bond interactions, pi-pi stacking, cation-pi stacking interactions.
How significant are the hydrophobic interactions? Although the strength of a single hydrogen bond is much greater than a hydrophobic contact, the number of hydrophobic contacts is much higher compared to hydrogen bonds. So, i think the cumulative effect of these interactions may overweigh the effect of hydrogen bonds.
Also, are there any other crucial interactions to look at while analyzing a protein-ligand complex?
Thanks.
The protein-ligand binding free energy can be fully described with the contributions from electrostatic, pre-organized electrostatic, and non-electrostatic interactions. Electrostatic contribution (including hydrogen-bonding interactions) can be quantified with the Coulomb's potential. Non-electrostatic contribution can be quantified with the Lennard-Jones potential. Pre-organized electrostatic contribution can be quantified with the Coulomb's potential using geometries obtained by sampling the conformational space (molecular dynamics simulation) with the partial atomic charges of the ligand set to zero. The entropic contribution is implicitly included in the ensemble of geometries.
The relative importance of electrostatic and non-electrostatic contributions depends on the charge- and shape-complementarity of the interacting entities; pre-organized electrostatic contribution takes into account the relative stability of the properly oriented ligand-binding groups in the protein and in the bulk solvent.
A compensatory effect is often seen: a conformation with more favorable electrostatic interactions has less favorable non-electrostatic interactions, and vice versa.
Hydrogen bonds, π-stacking, π-cation interactions, Salt bridges, Water bridges and Halogen bonds are important interactions while predicting the binding energy. But the binding mechanisms come down to cavity exploration in which Hydrophobic interactions contribute heavily to the binding affinity of the docked complex, in a given solvent system as they are are entropy driven interactions. If you consider the contribution of one hydrophobic contact with one absolute Hydrogen bond, the difference is big enough, but when you consider the number of hydrophobic contacts verses the number of Hydrogen bonds, you'll find how contributing the hydrophobic interactions really are to the docked complex.
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