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Sulimov A.V.,Moscow State University | Zheltkov D.A.,Moscow State University | Oferkin I.V.,Dimonta Ltd | Kutov D.C.,Moscow State University | And 3 more authors.
Computational and Structural Biotechnology Journal | Year: 2017

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. © 2017 The Authors


Grigoriev F.V.,Moscow State University | Golovacheva A.Y.,Dimonta Ltd. | Romanov A.N.,Moscow State University | Kondakova O.A.,Moscow State University | And 7 more authors.
Structural Chemistry | Year: 2012

It is known that the HIV-1 integrase (IN) strand transfer inhibitors include the chelating fragments forming the coordinating bonds with two Mg 2+ ions placed in the IN active site. The subject of the article is the role of these coordination bonds on stability of ligand-IN complexes. For this purpose, a set of ligand-IN complexes was investigated theoretically and experimentally. The theoretical model is based on the quantum-chemistry calculations of coordinating bonds geometry and energy. Solvent effects were taking into account using the implicit water model and the two-stage calculation scheme developed previously. For the experimental part of our study a set of the ligands was synthesized, and their IC 50 values of IN inhibiting have been measured. It is shown that the main contribution to ligand-IN complexes stability is caused by the substitution of water molecules by the ligand in the first coordination sphere of two Mg 2+ ions, and the change in the polarization energy of the bulk water. It is shown, that acid-base equilibrium and tautomeric forms of the ligands should be taken into account to improve the prediction ability of the theoretical estimations. All these factors are controlled by the chelating fragments of the ligands. It is demonstrated that our theoretical approach based on the consideration of the coordinating bonds allows to separate active ligands (inhibitors) from inactive ones. © Springer Science+Business Media, LLC 2011.


Romanov A.N.,Moscow State University | Haula E.V.,RAS Semenov Institute of Chemical Physics | Fattakhova Z.T.,RAS Semenov Institute of Chemical Physics | Veber A.A.,RAS A.M. Prokhorov General Physics Institute | And 4 more authors.
Optical Materials | Year: 2011

The broadband NIR luminescence of subvalent bismuth species was demonstrated in partially reduced ZrF4-BiF3-NaF and ZrF4-BiF3-BaF2 fluoride glasses. The parameters of luminescence were reported and compared with luminescence from other bismuth-doped materials. Since fluoride glass compositions are based on strong Lewis acids (ZrF4 in present case) they can stabilize NIR photoluminescent subvalent bismuth species. © 2011 Elsevier B.V. All rights reserved.


Romanov A.N.,Moscow State University | Fattakhova Z.T.,RAS Semenov Institute of Chemical Physics | Zhigunov D.M.,Dimonta Ltd. | Korchak V.N.,RAS Semenov Institute of Chemical Physics | Sulimov V.B.,Moscow State University
Optical Materials | Year: 2011

Creation of bismuth-containing near-infrared (NIR) luminescent centers by synproportionation reaction of Bi3+ and Bi0 was demonstrated in borate and phosphate glasses. This finding is discussed in the light of low-valence nature of bismuth NIR-luminescent centers. The experimental data is consistent with the hypothesis of univalent Bi+ (and, possible, subvalent cluster Bi ions) as a source of NIR luminescence. The dependence of Bi luminescent centers stability on oxoacidity of glass melts was discussed. © 2010 Elsevier B.V. All rights reserved.


Basilevsky M.V.,RAS Institute of Applied Mechanics | Grigoriev F.V.,Moscow State University | Nikitina E.A.,Dimonta LLC | Leszczynski J.,Jackson State University
Journal of Physical Chemistry B | Year: 2010

The modification of the electrostatic continuum solvent model considered in the present work is based on the exact solution of the Poisson equation, which can be constructed provided that the dielectric permittivity e of the total solute and solvent system is an isotropic and continuous spatial function. This assumption allows one to formulate a numerically efficient and universal computational scheme that covers the important case of a variable e function inherent to the solvent region. The obtained type of solution is unavailable for conventional dielectric continuum models such as the Onsager and Kirkwood models for spherical cavities and the polarizable continuum model (PCM) for solute cavities of general shape, which imply that e is discontinuous on the boundary confining the excluded volume cavity of the solute particle. Test computations based on the present algorithm are performed for water and several nonaqueous solvents. They illustrate specific features of this approach, called the "smooth boundary continuum model" (SBCM), as compared to the PCM procedure, and suggest primary tentative results of its parametrization for different solvents. The calculation for the case of a binary solvent mixture with variable e in the solvent space region demonstrates the applicability of this approach to a novel application field covered by the SBCM. © 2010 American Chemical Society.


Grigoriev F.V.,Dimonta Ltd. | Grigoriev F.V.,Moscow State University | Sulimov V.B.,Dimonta Ltd. | Sulimov V.B.,Moscow State University
Molecular Simulation | Year: 2016

A simple combined water model (SCW model) for the calculation of the hydration free energy is presented. In the frame of the model a solute is placed in the centre of the spherical cavity with explicit water molecules, which are considered at the atomistic level. Rigid wall potential at the boundary of the cavity restricts the moving of the explicit water molecules. Water outside the sphere is considered as the conducting continuum (implicit part of the model). Simulation is performed in the frame of the NVT ensemble (constant number of particles, volume and temperature), density of water is fixed and equal to experimental value 1 g/cm3. The energy of electrostatic interaction of atomic point charges of the explicit water molecules with conducting continuum is calculated analytically by means of the image charges method. It provides high computational efficiency of the SCW model. For the averaging of the calculated thermodynamic and structural values over microstates of the system the thermodynamic integration method is used. The possible using of SCW for the docking problem is discussed. © 2016 Informa UK Limited, trading as Taylor & Francis Group


Oferkin I.V.,Dimonta Ltd. | Zheltkov D.A.,Moscow State University | Tyrtyshnikov E.E.,Moscow State University | Sulimov A.V.,Moscow State University | And 2 more authors.
Bulletin of the South Ural State University, Series: Mathematical Modelling, Programming and Computer Software | Year: 2015

Effectiveness of modern rational new drugs development is connected with accurate modelling of binding between target-proteins responsible for the disease and small molecules (ligands) candidates to become drugs. The main modeling tools are docking programs for positioning of the ligands in the target proteins. Ligand positioning is realized in the frame of the docking paradigm: the ligand binds to the protein in the pose corresponding to the global energy minimum on the complicated multidimensional energy surface of the protein-ligand system. Docking algorithm on the base of the novel method of tensor train global optimization is presented. The respective novel docking program SOL-T is validated on the set of 30 protein-ligand complexes with known 3D structures. The energy of the protein-ligand system is calculated in the frame of MMFF94 force field. SOL-T performance is compared with the results of exhaustive low energy minima search carried out by parallel FLM docking program on the base of Monte Carlo method using large supercomputer resources. It is shown that SOL-T docking program is about 100 times faster than FLM program, and SOL-T is able to find the global minimum (found by FLM docking program) for 50% of investigated protein-ligand complexes. Dependence of SOL-T performance on the rank of tensor train decomposition is investigated, and it is shown that SOL-T with rank 16 has almost the same performance as SOL-T with rank 64. It is shown that the docking paradigm is true not for all investigated complexes in the frame of MMFF94 force field.


Oferkin I.V.,Dimonta Ltd. | Katkova E.V.,Moscow State University | Sulimov A.V.,Moscow State University | Kutov D.C.,Moscow State University | And 3 more authors.
Advances in Bioinformatics | Year: 2015

The adequate choice of the docking target function impacts the accuracy of the ligand positioning as well as the accuracy of the protein-ligand binding energy calculation. To evaluate a docking target function we compared positions of its minima with the experimentally known pose of the ligand in the protein active site. We evaluated five docking target functions based on either the MMFF94 force field or the PM7 quantum-chemical method with or without implicit solvent models: PCM, COSMO, and SGB. Each function was tested on the same set of 16 protein-ligand complexes. For exhaustive low-energy minima search the novel MPI parallelized docking program FLM and large supercomputer resources were used. Protein-ligand binding energies calculated using low-energy minima were compared with experimental values. It was demonstrated that the docking target function on the base of the MMFF94 force field in vacuo can be used for discovery of native or near native ligand positions by finding the low-energy local minima spectrum of the target function. The importance of solute-solvent interaction for the correct ligand positioning is demonstrated. It is shown that docking accuracy can be improved by replacement of the MMFF94 force field by the new semiempirical quantum-chemical PM7 method. © 2015 Igor V. Oferkin et al.


PubMed | Moscow State University and Dimonta Ltd.
Type: Journal Article | Journal: Biomeditsinskaia khimiia | Year: 2015

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.


PubMed | Moscow State University and Dimonta Ltd.
Type: | Journal: Advances in bioinformatics | Year: 2015

The adequate choice of the docking target function impacts the accuracy of the ligand positioning as well as the accuracy of the protein-ligand binding energy calculation. To evaluate a docking target function we compared positions of its minima with the experimentally known pose of the ligand in the protein active site. We evaluated five docking target functions based on either the MMFF94 force field or the PM7 quantum-chemical method with or without implicit solvent models: PCM, COSMO, and SGB. Each function was tested on the same set of 16 protein-ligand complexes. For exhaustive low-energy minima search the novel MPI parallelized docking program FLM and large supercomputer resources were used. Protein-ligand binding energies calculated using low-energy minima were compared with experimental values. It was demonstrated that the docking target function on the base of the MMFF94 force field in vacuo can be used for discovery of native or near native ligand positions by finding the low-energy local minima spectrum of the target function. The importance of solute-solvent interaction for the correct ligand positioning is demonstrated. It is shown that docking accuracy can be improved by replacement of the MMFF94 force field by the new semiempirical quantum-chemical PM7 method.

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