Relative contributions of desolvation, inter‐ and intramolecular interactions to binding affinity in protein kinase systems

Abstract

In several previous studies, we performed sensitivity analysis to gauge the relative importance of different atomic partial charges in determining protein-ligand binding. In this work, we gain further insights by decomposing these results into three contributions: desolvation, intramolecular interactions, and intermolecular interactions, again based on a Poisson continuum electrostatics model. Three protein kinase-inhibitor systems have been analyzed: CDK2-deschloroflavopiridol, PKA-PKI, and LCK-PP2. Although our results point out the importance of specific intermolecular interactions to the binding affinity, they also reveal the remarkable contributions from the solvent-mediated intramolecular interactions in some cases. Thus, it is necessary to look beyond analyzing protein-ligand interactions to understand protein-ligand recognition or to gain insights into designing ligands and proteins. In analyzing the contributions of the three components to the overall binding free energy, the PKA-PKI system with a much larger ligand was found to behave differently from the other two systems with smaller ligands. In the former case, the intermolecular interactions are very favorable, and together with the favorable solvent-mediated intramolecular interactions, they overcome the large desolvation penalties to give a favorable electrostatics contribution to the overall binding affinity. On the other hand, the other two systems with smaller ligands only present modest intermolecular interactions and they are not or are only barely sufficient to overcome the desolvation penalty even with the aid of the favorable intramolecular contributions. As a result, the binding affinity of these two systems do not or only barely benefit from electrostatics contributions.

Probing Molecular Docking in a Charged Model Binding Site

“…Considering their small size, the enriched ligands are diverse and include disubstituted pyridines (14-17, 20, 25), pyrimidines (18,19,23), amidines (21,22), alcohols (24,26,28), and non-aromatic ligands (22) ( Table 2), none of which had previously been discovered. That said, all of these molecules are small and cationic; could they have been found by simpler methods, such as chemical similarity?…”

“…30 24,25,28,33, and 34 were soaked overnight by adding 1 ml of 100 mM stock solution dissolved in water to the mother liquor. Compounds 15,21,22,25,and 27 were soaked for 1 h at a concentration of 50 mM in 25% MPD, and compounds 14 and 30 for 1 h at a concentration of 50 mM in 125 mM acetate buffer (pH 4.5) containing 25% MPD. Compounds 32 and 36 were soaked in both the MPD buffer and the acetate buffer.…”

“…These include receptor and ligand desolvation, other entropic contributions, polar and non-polar interactions, the hydrophobic effect, and receptor flexibility, among others. 21,22 Therefore, it would be useful to have model systems that are simple enough to allow one to separate the different energetic contributions and thereby isolate the effect of individual terms in a scoring function.…”

Free Energy Calculations: Approximate Methods for Biological Macromolecules

“…This was especially useful because the most important interactions were not all evident from visual inspection of the structures. Sims et al [122] analyzed protein kinase-inhibitor binding, and underlined the importance of solvent-mediated intramolecular interactions. Roux and McKinnon [123] analyzed the selectivity of the KcsA potassium channel in terms of particular free energy components, including desolvation components and direct interactions of the ion with the channel helices.…”

Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study

“…Nevertheless, the lack of binding affinity of the nitrenium ion might be also explained by a desolvation penalty higher than that of clozapine due to the presence of a double positive charge. Indeed, contribution of desolvation to binding affinity was proposed in some protein-ligand complexes [34][35][36][37].…”