Ligand Mapping on Protein Surfaces by the 3D-RISM Theory: Toward Computational Fragment-Based Drug Design

Abstract

In line with the recent development of fragment-based drug design, a new computational method for mapping of small ligand molecules on protein surfaces is proposed. The method uses three-dimensional (3D) spatial distribution functions of the atomic sites of the ligand calculated using the molecular theory of solvation, known as the 3D reference interaction site model (3D-RISM) theory, to identify the most probable binding modes of ligand molecules. The 3D-RISM-based method is applied to the binding of several small organic molecules to thermolysin, in order to show its efficiency and accuracy in detecting binding sites. The results demonstrate that our method can reproduce the major binding modes found by X-ray crystallographic studies with sufficient precision. Moreover, the method can successfully identify some binding modes associated with a known inhibitor, which could not be detected by X-ray analysis. The dependence of ligand-binding modes on the ligand concentration, which essentially cannot be treated with other existing computational methods, is also investigated. The results indicate that some binding modes are readily affected by the ligand concentration, whereas others are not significantly altered. In the former case, it is the subtle balance in the binding affinity between the ligand and water that determines the dominant ligand-binding mode.

The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation

“…The 3D reference interaction site model (3D-RISM) theory is an integral equation theory based on statistical mechanics (Imai et al, 2009), which generates accurate 3D solvent distribution function of water molecules around and inside a biomolecule of interest. The Placevent algorithm (Sindhikara et al, 2012) was then exploited to translate the continuous distributions from the 3D-RISM calculation to explicit water molecules.…”

Solvation Thermodynamics of Organic Molecules by the Molecular Integral Equation Theory: Approaching Chemical Accuracy

“…The EC-RISM approach was successfully applied for prediction of tautomer ratios, 21 studying solvation effects on NMR chemical shifts 170 and prediction of acidity constants of organic molecules in dimethyl sulfoxide (DMSO) solution. 13,196,209,290 which are difficult to study satisfactorily with explicit solvent simulation methods. The combination of a conformational sampling method with RISM allows a detailed description of the structure and flexibility of molecules in solution.…”

Role of Water in Ligand Binding to Maltose-Binding Protein: Insight from a New Docking Protocol Based on the 3D-RISM-KH Molecular Theory of Solvation

“…High density peaks on these maps may correspond to tightly bound (structural) water molecules at the macromolecular surface. It was shown that there is a good agreement between the 3D-RISM-KH predictions on structural water and X-ray experimental data, 43 as well as between 3D-RISM-KH and MD results on solvation structure of proteins. 41,42 We use the 3D-RISM-KH molecular theory of solvation to calculate 3D water density maps around the open state of MBP and to predict possible locations of tightly bound water molecules at the protein surface.…”