Abstract
Water molecules play important roles in all biochemical processes. Therefore, it is of key importance to obtain information of the structure, dynamics, and thermodynamics of water molecules around proteins. Numerous computational methods have been suggested with this aim. In this study, we compare the performance of conventional and grand-canonical Monte Carlo (GCMC) molecular dynamics (MD) simulations to sample the water structure, as well GCMC and grid-based inhomogeneous solvation theory (GIST) to describe the energetics of the water network. They are evaluated on two proteins: the buried ligand-binding site of a ferritin dimer and the solvent-exposed binding site of galectin-3. We show that GCMC/MD simulations significantly speed up the sampling and equilibration of water molecules in the buried binding site, thereby making the results more similar for simulations started from different states. Both GCMC/MD and conventional MD reproduce crystal-water molecules reasonably for the buried binding site. GIST analyses are normally based on restrained MD simulations. This improves the precision of the calculated energies, but the restraints also significantly affect both absolute and relative energies. Solvation free energies for individual water molecules calculated with and without restraints show a good correlation, but with large quantitative differences. Finally, we note that the solvation free energies calculated with GIST are ∼5 times larger than those estimated by GCMC owing to differences in the reference state.
Highlights
All biochemical processes take place in a water solution
This typically involves carrying out Monte Carlo (MC) moves that insert and delete water molecules to/from a predefined region of interest (ROI), allowing the exchange of waters between this region and bulk water to be Inhomogeneous fluid solvation theory is a method developed for the thermodynamic analysis of water sites observed in molecular dynamics (MD) simulations.[12−14] This method calculates the binding free energy of a water site, including the entropic contributions, making use of correlation functions of the translational and rotational behavior of water molecules
The grand-canonical Monte Carlo (GCMC) box was centered around the ligand binding site with dimensions of 26.3 Å × 12.9 Å × 15.0 Å, whereas two different sizes were used for the grid-based inhomogeneous solvation theory (GIST) analysis, as detailed in Table 2, with a spacing of 0.5 Å between voxels
Summary
All biochemical processes take place in a water solution. It is well-known that water has unusual properties and has a substantial influence on biochemical reactions, for example, by providing a large dielectric screening, by forming strong hydrogen bond, and by the hydrophobic effect.[1−4] it is important to understand the effect of water molecules in various processes in order to make it possible to manipulate them, for example, in the design of improved catalysts or more effective drugs. The sampling of these calculations can Protein-bound water molecules often show slow exchange with bulk solvent, which can make such exchanges very slow to equilibrate during computer simulations.[27] Grand canonical be further improved by allowing replica exchanges between simulations at different B values.[20] Grid-Based Inhomogeneous Solvation Theory methods attempt to increase the frequency of these events by allowing the number of particles present in a simulation to fluctuate according to a user-specified chemical potential, which is constrained (along with the temperature and volume) This typically involves carrying out MC moves that insert and delete water molecules to/from a predefined ROI, allowing the exchange of waters between this region and bulk water to be Inhomogeneous fluid solvation theory is a method developed for the thermodynamic analysis of water sites observed in MD simulations.[12−14] This method calculates the binding free energy of a water site, including the entropic contributions, making use of correlation functions of the translational and rotational behavior of water molecules. The GCMC box was centered around the ligand binding site with dimensions of 26.3 Å × 12.9 Å × 15.0 Å, whereas two different sizes were used for the GIST analysis (to include all conformations of the ligands), as detailed in Table 2, with a spacing of 0.5 Å between voxels
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