A method and program for mass quantum chemical calculations of protein—ligand docking complexes

Anikin, N. A.; Mendkovich, A. S.; Kuzminskiy, M. B.; Andreev, A. M.

doi:10.1007/s11172-008-0067-y

Cited by 5 publications

(3 citation statements)

References 15 publications

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“…They have been applied to docking and scoring studies frequently at the semiempirical level of theory. [18–25] However, as was shown before for PL interaction energies of truncated PL models,[26] to obtain their high performance level, semiempirical methods sacrifice their overall accuracy. Linear scaling approaches enable to perform correlated quantum chemical calculations for macromolecular systems, too.…”

Section: Introductionmentioning

confidence: 99%

Fully ab initio protein‐ligand interaction energies with dispersion corrected density functional theory

2012

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Dispersion corrected density functional theory (DFT-D3) is used for fully ab initio protein-ligand (PL) interaction energy calculation via molecular fractionation with conjugated caps (MFCC) and applied to PL complexes from the PDB comprising 3680, 1798, and 1060 atoms. Molecular fragments with n amino acids instead of one in the original MFCC approach are considered, thereby allowing for estimating the three-body and higher many-body terms. n > 1 is recommended both in terms of accuracy and efficiency of MFCC. For neutral protein side-chains, the computed PL interaction energy is visibly independent of the fragment length n. The MFCC fractionation error is determined by comparison to a full-system calculation for the 1060 atoms containing PL complex. For charged amino acid side-chains, the variation of the MFCC result with n is increased. For these systems, using a continuum solvation model with a dielectricity constant typical for protein environments (ϵ = 4) reduces both the variation with n and improves the stability of the DFT calculations considerably. The PL interaction energies for two typical complexes obtained ab initio for the first time are found to be rather large (-30 and -54 kcal/mol).

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Section: Introductionmentioning

confidence: 99%

Fully ab initio protein‐ligand interaction energies with dispersion corrected density functional theory

2012

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“…The accuracy of our tech nique appeared to be rather high, viz., the root mean square error in the interaction energy was 0.4 kcal mol -1 (0.02 eV). 35 Since in large scale calculations of docking complexes an important role is played by statistical analy sis of results obtained, 6,7,13,14 a high coefficient of linear correlation between the results obtained using our tech nique and the reference method (0.997) should also me mentioned.…”

Section: Testing Of the Methodsmentioning

confidence: 81%

“…35 Using the АМ1 semiempirical Hamiltonian, we calculated complexes of human immunoglobulin and some smaller proteins with an immune suppressor IMMUNOPHILIN FKBP 12 (FKB, 1663 atoms) and pancreatic ribonuclease (1852 at oms). Ligand molecules (in particular, dinucleotides with DNA/RNA bases and a phosphodiester bridge and mono nucleosides) comprised 30 to 144 atoms.…”

Section: Testing Of the Methodsmentioning

confidence: 99%

A fast method of large-scale serial semiempirical calculations of docking complexes

et al. 2008

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A brief survey of the state of the art in methods of calculations of protein-ligand interaction energies in docking complexes is presented. A new computational technique is proposed that allows one to fundamentally improve the performance of large scale serial calculations of docking complexes using the AM1/PM3 semiempirical methods. The technique explicitly al lows for a specific feature of docking problems, viz., the need for calculating numerous ligand complexes with a specified protein whose noninteracting part remains "frozen" during computa tions. The interaction energies calculated using the new method differ only slightly from the results of complete АМ1 calculations and the performance attained is high enough to solve practical drug design problems.Key words: large scale calculations of docking complexes, fast quantum chemical calcula tions, semiempirical methods.The determination of activity of relatively small ligand molecules (prototypes of active principles of drugs) in the interaction with large protein molecules is a key problem in biochemistry. Knowledge of energies of the interaction of a protein with ligands for very large ligand collections is of crucial importance for efficient targeted drug design. Meanwhile, the design of pharmaceuticals including high ly specific and even individually "tuned" ones (in the fu ture) belongs to scientific challenges of crucial importance.It is appropriate to begin large scale preliminary screening of ligands to choose best candidates from the standpoint of ligand-protein interactions with theo retical studies using computer simulation followed by more expensive and long term experiments with the ligands chosen.The increasing use of computer assisted docking* is due to important role of this technique for novel drug de sign technologies. The demand of rapidly developing phar maceutical industry for less expensive drug design, which becomes increasingly more complicated 1 against the back ground of exponentially increasing computer performance, makes the docking (or, more generally, computer assisted * From this point on we use the term "docking" in a broad sense including the determination of ligand arrangement in the protein cavity and the energy of the protein-ligand interaction.

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Fast method for quantum chemical calculations of large molecules with the approximation of the DFT Hamiltonian

et al. 2014

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The fundamentally new method NESE is proposed for quantum chemical calculations of large molecules, which employs the approximation of the Hamiltonian of the commonly used DFT method and is as fast as the AM1 and PM3 semi empirical methods or the DFTB method. The parameters for the new method were chosen by the least squares method based on the comparison of its matrix elements with the reference DFT/PBE Hamiltonian. The initial non iterative version NESE 0 was computer implemented and approved on many thousands of various molecules containing H, C, N, and O atoms. The NESE 0 method moderately outper forms the DFTB approach and is an order of magnitude better than the AM1, PM3, and PM6 levels in reproducing the one electron energies calculated in terms of the DFT/PBE. Key words: approximate DFT Hamiltonian, fast quantum chemical methods, large mole cules, selection of parameters.The computer modeling of large biological molecules and nanostructures at the quantum chemical level allows researchers to reduce the time of the design of such ob jects, as well as the time of obtaining adequate informa tion on the quantum electronic properties (as opposed to those obtained by molecular mechpanics) and the spatial structures of the newly designed and the already available bio and nanostructures. Experiments for such structures become more and more expensive, while the cost of calcu lations being rapidly reduced. This promising field of high performance calculations is very important, for example, in solving problems of the computer drug design. In the latter case, it is necessary to perform calculations of giant molecules, which requires large computer resources even when employing commonly used and reasonably accurate density functional theory (DFT) methods, not to mention more precise and sophisticated approaches. Hence, semi empirical methods, such as AM1, 1 PM3, 2 and PM6, 3 as well as the approximate DFT method SCC DFTB (self consistent charge density functional tight binding) meant for fast calculations of large systems, 4 were em ployed as alternative approaches.Earlier, we have achieved the record speed for a num ber of simple semi empirical quantum chemical meth ods. 5,6 This allows one to perform large scale calculations (thousands of complexes, each consisting of thousands of atoms) using standard computers. However, the need arises for fast calculations with an accuracy of modern DFT methods widely used in far less large scale calculations. In the present work, we propose a new quantum chemical method for calculations of large molecules, which is al * On the occasion of the 80th anniversary of the N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences.

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A method and program for mass quantum chemical calculations of protein—ligand docking complexes

Cited by 5 publications

References 15 publications

Fully ab initio protein‐ligand interaction energies with dispersion corrected density functional theory

Fully ab initio protein‐ligand interaction energies with dispersion corrected density functional theory

A fast method of large-scale serial semiempirical calculations of docking complexes

Fast method for quantum chemical calculations of large molecules with the approximation of the DFT Hamiltonian

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