[Docking with combined use of a force field and a quantum-chemical method]. / Doking s kombinirovannym primeneniem silovogo polia i kvantovo-khimicheskogo metoda.

The paper presents the results concerning the application of docking programs FLM to combined use of the MMFF94 force field and the semiempirical quantum-chemical method PM7 in the docking procedure. At the first step of this procedure a fairly wide range of low-energy minima of the protein-ligand complex is found in the frame of the MMFF94 force field using the FLM program. The energies of all these minima are recalculated using the PM7 method and the COSMO solvent continuum model at the second step. On the basis of these calculations the deepest minimum of the protein-ligand energy, calculated by the PM7 method with COSMO solvent, is determined, which gives the position of the ligand closest to its position in the crystal of the protein-ligand complex. It is shown that the first step of the combined procedure is performed more quickly and more efficiently in vacuum, rather than with a solvent model.

[Supercomputer investigation of the protein-ligand system low-energy minima].

The accuracy of the protein-ligand binding energy calculations and ligand positioning is strongly influenced by the choice of the docking target function. This work demonstrates the evaluation of the five different target functions used in docking: functions based on MMFF94 force field and functions based on PM7 quantum-chemical method accounting or without accounting the implicit solvent model (PCM, COSMO or SGB). For these purposes the ligand positions corresponding to the minima of the target function and the experimentally known ligand positions in the protein active site (crystal ligand positions) were compared. Each function was examined on the same test-set of 16 protein-ligand complexes. The new parallelized docking program FLM based on Monte Carlo search algorithm was developed to perform the comprehensive low-energy minima search and to calculate the protein-ligand binding energy. This study demonstrates that the docking target function based on the MMFF94 force field can be used to detect the crystal or near crystal positions of the ligand by the finding the low-energy local minima spectrum of the target function. The importance of solvent accounting in the docking process for the accurate ligand positioning is also shown. The accuracy of the ligand positioning as well as the correlation between the calculated and experimentally determined protein-ligand binding energies are improved when the MMFF94 force field is substituted by the new PM7 method with implicit solvent accounting.