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.
Adekvatnyĭ vybor tselevoĭ funktsii pri provedenii dokinga mozhet znachitel'no povliiat' kak na tochnost' pozitsionirovaniia liganda, tak i na tochnost' raschetov énergii sviazyvaniia belka i liganda. V dannoĭ rabote provedena otsenka piati razlichnykh tselevykh funktsiĭ, primeniaemykh v dokinge, vkliuchaia funktsii, baziruiushchiesia na silovom pole MMFF94, a takzhe na kvantovokhimicheskom metode PM7, kak s uchetom, tak i bez ucheta rastvoritelia (v ramkakh modeleĭ rastvoritelia PCM, COSMO, SGB). Dlia provedeniia podobnoĭ otsenki my sravnili polozheniia ligandov v minimumakh funktsiĭ s éksperimental'no izvestnymi polozheniiami liganda v aktivnom tsentre belka (tak nazyvaemymi kristallicheskimi polozheniiami liganda), a takzhe sravnili poluchivshiesia v rezul'tate vychisleniĭ svobodnye énergii sviazyvaniia s énergiiami, poluchennymi iz éksperimental'nykh dannykh. Kazhdaia iz funktsiĭ byla issledovana na testovom nabore, sostoiashchem iz 16 kompleksov belok-ligand. Dlia nakhozhdeniia minimumov byla razrabotana novaia parallel'naia programma dokinga FLM, ispol'zuiushchaia algoritm Monte-Karlo i osushchestvliaiushchaia ischerpyvaiushchiĭ poisk nizkoénergeticheskikh minimumov, a takzhe vychislenie svobodnoĭ énergii sviazyvaniia. Poluchennye dannye pokazyvaiut, chto tselevaia funktsiia dokinga na osnove silovogo polia MMFF94 v vakuume mozhet byt' ispol'zovana dlia obnaruzheniia kristallicheskogo ili blizkikh k nemu pozitsiĭ liganda. Uluchshenie kak tochnosti pozitsionirovaniia liganda, tak i korreliatsii znacheniĭ énergiĭ sviazyvaniia so znacheniiami, poluchennymi v éksperimente, bylo pokazano pri zamene silovogo polia MMFF94 na novyĭ metod PM7 s uchetom vody v neiavnoĭ modeli COSMO.
Keywords: docking; force field; high-performance computing; molecular modeling; multiwell approximation; quantum chemistry.