Evaluation of the novel algorithm of flexible ligand docking with moveable target-protein atoms

Abstract

We present the novel docking algorithm based on the Tensor Train decomposition and the TT-Cross global optimization. The algorithm is applied to the docking problem with flexible ligand and moveable protein atoms. The energy of the protein-ligand complex is calculated in the frame of the MMFF94 force field in vacuum. The grid of precalculated energy potentials of probe ligand atoms in the field of the target protein atoms is not used. The energy of the protein-ligand complex for any given configuration is computed directly with the MMFF94 force field without any fitting parameters. The conformation space of the system coordinates is formed by translations and rotations of the ligand as a whole, by the ligand torsions and also by Cartesian coordinates of the selected target protein atoms. Mobility of protein and ligand atoms is taken into account in the docking process simultaneously and equally. The algorithm is realized in the novel parallel docking SOL-P program and results of its performance for a set of 30 protein-ligand complexes are presented. Dependence of the docking positioning accuracy is investigated as a function of parameters of the docking algorithm and the number of protein moveable atoms. It is shown that mobility of the protein atoms improves docking positioning accuracy. The SOL-P program is able to perform docking of a flexible ligand into the active site of the target protein with several dozens of protein moveable atoms: the native crystallized ligand pose is correctly found as the global energy minimum in the search space with 157 dimensions using 4700 CPU ∗ h at the Lomonosov supercomputer.

Development of docking programs for Lomonosov supercomputer

“…This supercomputer program (15,18,19) is also the gridless generalized docking program of the new generation. As the FLM program does SOL-P performs the search for low energy minima spectra of molecular systems, in particular, the proteinligand complexes.…”

“…If the grid is fine enough the solutions of the continuous and discrete global optimization problems will be close to one another. The docking problem which is the global minimization problem can be easily transformed to the global maximization problem and we find that it is convenient to apply the magnitude maximization to the following functional (18):…”

“…Two approaches for the selection of moveable protein atoms are used. The first one is applying the Mark-PMA program (18) which marks protein atoms to be moveable relying upon their proximity to the native crystallized ligand conformation. It was shown previously (18) that in many cases successful docking is reached when from 25 to 35 protein atoms became moveable using marking by this program.…”

“…We present here a short descriptions of our docking programs SOL (1,12,13), FLM (14)(15)(16)(17) and SOL-P (15,18,19) developed in Lomonosov Moscow State University for the computing resources available in this university during the recent 15 years including the Lomonosov-2 supercomputer. Some applications of these docking programs are presented also in short.…”

Modern methods for the development of new drugs that affect the hemostatic system

“…В связи с попытками разобраться в причинах, ограничивающих точность докинга [5], недавно были разработаны несколько суперкомпьютерных параллельных (многопроцессорных) программ докинга -FLM [48][49][50], SOL-T [51] и SOL-P [52,53], в которых не используется сетка заранее рассчитанных потенциалов взаимодействия атомов лиганда с белком, и при выполнении докинга, то есть в процессе глобальной оптимизации, энергия комплекса «белок-лиганд» для любой его конфигурации вычисляется без всяких упрощений и ограничений -прямо в рамках заданного силового поля. Эти программы названы программами прямого (или бессеточного) обобщенного докинга, причем слово «обобщенный» отражает тот факт, что цель выполнения этих программ -не просто нахождение глобального минимума энергии, как это делает большинство описанных выше программ докинга, а нахождение всего спектра низкоэнергетических минимумов комплекса «белок-лиганд», включая, конечно, и глобальный минимум.…”