ABSTRACT
To model binding of ligands to proteins, one has to go beyond simple molecular mechanics. This is because of the relative orientations of ligands and the target proteins, which must be sampled with special care. For this purpose, protein-docking methods have been developed. During the last few decades, protein docking has become one of the most important molecular modeling methods used in the pharmaceutical industry.1-5 A number of academic and commercial programs have been developed, and their performance has been improved steadily. The state-of-the-art docking programs can reproduce a set of experimentally determined structures within 2 Å of root mean square deviation (RMSD) close to 80% of the time. To achieve such accuracy, docking programs exploit various empirical scoring schemes, as well as energy-based ones. For the electrostatic energy portion of scoring, most of the current docking methods use force eld-based xed electric charges for both protein and ligand atoms.2,6-9 It has been shown that a variable charge model using the combined quantum mechanics/molecular mechanics (QM/MM) methods for
9.1 Background and Introduction ....................................................................... 253 9.2 Methods ........................................................................................................ 255
9.2.1 Docking Method ............................................................................... 255 9.2.2 QM/MM Docking ............................................................................256 9.2.3 Charge Fitting ...................................................................................256 9.2.4 Choice of Ligand-Protein Complexes .............................................. 257
9.3 Results and Discussion ................................................................................. 258 9.3.1 Including Only Metal Ions in the QM Region .................................. 258 9.3.2 Extended QM/MM Docking Protocol .............................................. 259 9.3.3 Test of “Practical” Protocol .............................................................. 261 9.3.4 Test of Docking Accuracy and Scoring Reliability on Matrix
Metalloproteinase ............................................................................. 262 9.4 Conclusion and Future Directions ................................................................264 References ..............................................................................................................265
