Protein–Ligand Electrostatic Binding Free Energies from Explicit and Implicit Solvation

Abstract

Accurate yet efficient computational models of solvent environment are central for most calculations that rely on atomistic modeling, such as prediction of protein-ligand binding affinities. In this study, we evaluate the accuracy of a recently developed generalized Born implicit solvent model, GBNSR6 (Aguilar et al. J. Chem. Theory Comput. 2010, 6, 3613–3639), in estimating the electrostatic solvation free energies (ΔGpol) and binding free energies (ΔΔGpol) for small protein-ligand complexes. We also compare estimates based on three different explicit solvent models (TIP3P, TIP4PEw and OPC). The two main findings are as follows. First, the deviation (RMSD=7.04 kcal/mol) of GBNSR6 binding affinities from commonly used TIP3P reference values is comparable to the deviations between explicit models themselves, e.g. TIP4PEw vs. TIP3P (RMSD=5.30 kcal/mol). A simple uniform adjustment of the atomic radii by a single scaling factor reduces the RMS deviation of GBNSR6 from TIP3P to within the above “error margin” – differences between ΔΔGpol estimated by different common explicit solvent models. The simple radii scaling virtually eliminates the systematic deviation (ΔΔGpol) between GBNSR6 and two out of the three explicit water models, and significantly reduces the deviation from the third explicit model. Second, the differences between electrostatic binding energy estimates from different explicit models is disturbingly large; for example, the deviation between TIP4PEw and TIP3P estimates of ΔΔGpol values can be up to ~50% in relative error, or ~9 kcal/mol in absolute error, which is significantly larger than “chemical accuracy” goal of ~1 kcal/mol. The absolute ΔGpol calculated with different explicit models could differ by tens of kcal/mol. These discrepancies point to unacceptably high sensitivity of binding affinity estimates to the choice of common explicit water models. The absence of a clear “gold standard” among these models strengthens the case for the use of accurate implicit solvation models for binding energetics, which may be orders of magnitude faster.

Accuracy comparison of several common implicit solvent models and their implementations in the context of protein-ligand binding

“…[38]. In the case of proteins and protein-ligand complexes the explicit water model was used as described in [22] to perform calculations with the Amber package [46] by the thermodynamic integration (TI) method implemented in the sander program (the Amber package). Obtained values of the solvation energy are used as reference data to evaluate the quality of implicit solvent models.…”

“…Convergence of the TI protocol and its sensitivity to the initial conditions were checked for two randomly selected complexes as it is described in [22]. For these complexes the calculations were repeated using the different random seeds, and it was notices that the obtained received differences didn't exceed a standard deviation for the calculated solvation energy values, which is of ±0.7 kcal/mol [22] for complexes and proteins.…”

“…For these complexes the calculations were repeated using the different random seeds, and it was notices that the obtained received differences didn't exceed a standard deviation for the calculated solvation energy values, which is of ±0.7 kcal/mol [22] for complexes and proteins. To confirm the convergence of the TI results the simulation time was extended from 2 to 5 nanoseconds, and it was observed that the resulting values of the solvation energies didn't exceed a standard deviation.…”

“…good correspondence of the calculated hydration energies to experimentally measured ones for a set of more than 400 small molecules [26]. Taking into account that DISOLV and MCBHSOLV programs are used successfully for new inhibitors development [32–34] at the post-processing stage [10] and in the gridless docking procedure [35] in the frame of the MMFF94 force field [31] there is a need to compare results of DISOLV and MCBHSOLV calculations with ones performed with other implicit solvent programs and parameterization methods [14, 20–22, 25] for same sets of molecules. Here we will also examine a relatively recent addition to the family of GB models, GBNSR6, which has already demonstrated high accuracy in estimates of hydration free energies of small molecules [14].…”

Insilico Studies of Oxime Prodrug of Gliclazide Against Sulphonylurea Receptors (Sur 1)

“…The most interesting case is the protein-ligand interaction, because of its applications in medicines. Ligand is a small molecule, which interacts with protein's binding sites [2]. Binding modes are several possible mutual conformations in which bindings may occur.…”