Optimal water networks in protein cavities with GAsol and 3D-RISM

Abstract

Supplementary data are available at Bioinformatics online.

Water envelope has a critical impact on the design of protein–protein interaction inhibitors

“…17 In a number of publications it was shown that this physically rigorous computational approach reproduced with high accuracy experimental data on the structure of solvation shells for various systems. [18][19][20] For PEX14 structures, we revealed an excellent agreement between the predicted water positions and high-resolution X-ray data (PDB ID = 5L87; res. = 0.87 Å, see Fig.…”

Instantaneous generation of protein hydration properties from static structures

“…15) was used to achieve convergence for hydration-site occupancy and thermodynamics predictions for solvent-exposed and occluded binding sites 20 . Using 3D-RISM site-distribution function [49][50][51] and GAsol 42 for initial placement of water molecules, WATsite then performs explicit water MD simulations of each protein. Finally, explicit water occupancy and free energy profiles of each hydration site (i.e., high wateroccupancy spot) in the binding site are computed.…”

“…10). Both of our methods were compared to WATsite 18 and GAsol (3D-RISM) 42 . It should be noted that WATsite had been previously tested to reproduce Xray water molecules 18,20,27 .…”

“…The binding site center was defined by superposing the holo form of the same proteins (with ligand present) onto the apo form and using the centroid of the aligned ligand as the center of the grids. We compared the performance of our method with two other methods: WATsite 18 (MD-based method) and hydration-site prediction generated from GAsol's clustering method on 3D-RISM grids 42 (grid-based method). All crystallographic water molecules and ions were removed as part of the protein preparation process.…”

Active learning strategies with COMBINE analysis: new tricks for an old dog

“…The taxanes set contains a series of complex natural product derivatives (macrocycles) but that has led to very successful COMBINE models in the past [19,20]. The BRD4-BD1 set is made of a congeneric series of pyridinone derivatives designed to interact with the complex combination of flexible residues and the "dry" water molecules network in the binding site of the bromodomain that recognizes an acetyl-lysine residue [36]. These two binding sites have very different properties in terms of electrostatics and shape and were chosen to obtain a general overview of the performance of AL-COMBINE models beyond the HIV-PR set.…”