Mixed implicit/explicit solvation models in quantum mechanical calculations of binding enthalpy for protein-ligand complexes

摘要

An approach to quantum mechanical investigation of interactions in protein-ligand complexes has been developed that treats the solvation effect in a mixed scheme combining implicit and explicit solvent models. In this approach, the first solvation shell of the solvent around the solute is modeled with a limited number of hydrogen bonded explicit solvent molecules. The influence of the remaining bulk solvent is treated as a surrounding continuum in the conductor-like screening model (COSMO). The enthalpy term of the binding free energy for the protein-ligand complexes was calculated using the semiempirical PM3 method implemented in the MOPAC package, applied to a trimmed model of the protein-ligand complex constructed with special rules. The dependence of the accuracy of binding enthalpy calculations on size of the trimmed model and number of optimized parameters was evaluated. Testing of the approach was performed for 1.2 complexes of different ligands with trypsin, thrombin, and ribonuclease with experimentally known binding enthalpies. The root-mean-square deviation (RMSD) of the calculated binding enthalpies from experimental data was found as similar to 1 kcal/mol over a large range. (c) 2006 Wiley Periodicals, Inc. Int J Quantum Chem 106: 1943-1963, 2006.