Importance of Polar Solvation for Cross-Reactivity of Antibody and Its Variants with Steroids

Abstract

Understanding the factors determining the binding of ligands to receptors in detail is essential for rational drug design. Here, the free energies of binding of the steroids progesterone (PRG) and 5β-androstane-3,17-dione (5AD) to the Diels-Alderase antibody 1E9, as well as the Leu(H47)Trp/Arg(H100)Trp 1E9 double mutant (1E9dm) and the corresponding single mutants, have been estimated and decomposed using the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method. Also the difference in binding free energies between the PRG-1E9dm complex and the complex of PRG with the antiprogesterone antibody DB3 have been evaluated and decomposed. The steroids bind less strongly to 1E9 than to DB3, but the mutations tend to improve the steroid affinity, in quantitative agreement with experimental data. Although the complexes formed by PRG or 5AD with 1E9dm and by PRG with DB3 have similar affinity, the binding mechanisms are different. Reduced van der Waals interactions as observed for 5AD-1E9dm versus PRG-1E9dm or for PRG-1E9dm versus PRG-DB3 are energetically compensated by an increased solvation of polar groups, partly contrasting previous conclusions based on structural inspection. Our study illustrates that deducing binding mechanisms from structural models alone can be misleading. Therefore, taking into account solvation effects as in MM-PBSA calculations is essential to elucidate molecular recognition.

Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir

“…However, the polar component of the solvation free energy and the entropy disfavor the complex formations. These findings agree with MM-PBSA studies for other protein-ligand complexes [48]. The individual components of the binding free energy are influenced by the protonation states of Asp25/Asp25 0 .…”

“…The ligand was assigned generalized amber force field (GAFF) [44] atom types, and AM1-BCC [45] atomic charges calculated with the antechamber [46] module of Amber [47]. Our previous work [48] shows that this charge scheme is suitable for this kind of study. The configurations were generated via simulations of the complexes in explicit water.…”

“…The range was obtained by replacing DDG bind by DDG bind AE seðDDG bind Þ; where seðDDG bind Þ denotes the standard error of the relative binding free energy. The same scheme was used to determine the range of r in our previous study [48]. The standard errors of the mean for the individual components to the binding free energy were computed by dividing the respective standard deviations by the square root of the number of configurations considered.…”

“…The enzyme active site is gated by two extended b hairpin loops (residues [46][47][48][49][50][51][52][53][54][55][56], known as the flap regions, which presumably open and close to allow entry and binding of drugs [4,5]. Three characteristic regions are observed in the flaps.…”

A study of the interaction between HIV-1 protease and C 2-symmetric inhibitors by computational methods

“…This implies that the formamide group can contribute large electrostatic energy, but this favorable energy is opposed by unfavorable polar solvation energies (ΔG pol ). As found for other systems [15,35,36], the unfavorable polar solvation energy is partially compensated by favorable electrostatic interaction energies. The sum of electrostatic energy and polar solvation energy (ΔG ele+pol ) is unfavorable for inhibitors binding to PR.…”