Calculation of protein–ligand binding affinities based on a fragment quantum mechanical method

Liu, Jinfeng; Wang, Xianwei; Zhang, John Z. H.; He, Xiao

doi:10.1039/c5ra20185c

Cited by 52 publications

(48 citation statements)

References 75 publications

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“…The electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method was employed to perform full QM calculations of electric field in KSI. The detailed description of the EE-GMFCC method can be found in our previous works [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. The calculations of the electrostatic potential by the EE-GMFCC method are the same as our previous work [ 16 ].…”

Section: Computational Approachesmentioning

confidence: 99%

An Ab Initio QM/MM Study of the Electrostatic Contribution to Catalysis in the Active Site of Ketosteroid Isomerase

Wang

2018

Molecules

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The electric field in the hydrogen-bond network of the active site of ketosteroid isomerase (KSI) has been experimentally measured using vibrational Stark effect (VSE) spectroscopy, and utilized to study the electrostatic contribution to catalysis. A large gap was found in the electric field between the computational simulation based on the Amber force field and the experimental measurement. In this work, quantum mechanical (QM) calculations of the electric field were performed using an ab initio QM/MM molecular dynamics (MD) simulation and electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method. Our results demonstrate that the QM-derived electric field based on the snapshots from QM/MM MD simulation could give quantitative agreement with the experiment. The accurate calculation of the electric field inside the protein requires both the rigorous sampling of configurations, and a QM description of the electrostatic field. Based on the direct QM calculation of the electric field, we theoretically confirmed that there is a linear correlation relationship between the activation free energy and the electric field in the active site of wild-type KSI and its mutants (namely, D103N, Y16S, and D103L). Our study presents a computational protocol for the accurate simulation of the electric field in the active site of the protein, and provides a theoretical foundation that supports the link between electric fields and enzyme catalysis.

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Section: Computational Approachesmentioning

confidence: 99%

An Ab Initio QM/MM Study of the Electrostatic Contribution to Catalysis in the Active Site of Ketosteroid Isomerase

Wang

2018

Molecules

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“…Antony and Grimme [ 28 ] also showed how DFT-D3 can be applied to complexes of up to a few thousand atoms via molecular fragmentation with conjugated caps (MFCC). For MFCC (further discussed in references [ 29 , 30 , 31 ]), the protein is decomposed into fragments, which are then capped with typical end groups. MFCC is found to work well for the artificial case of a neutral peptide, but convergence problems are found for fragments with multiple charges.…”

Section: Dispersion-corrected Density Functional Theory (Dft-d) Anmentioning

confidence: 99%

Recent Progress in Treating Protein–Ligand Interactions with Quantum-Mechanical Methods

Yilmazer

Korth

2016

IJMS

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We review the first successes and failures of a “new wave” of quantum chemistry-based approaches to the treatment of protein/ligand interactions. These approaches share the use of “enhanced”, dispersion (D), and/or hydrogen-bond (H) corrected density functional theory (DFT) or semi-empirical quantum mechanical (SQM) methods, in combination with ensemble weighting techniques of some form to capture entropic effects. Benchmark and model system calculations in comparison to high-level theoretical as well as experimental references have shown that both DFT-D (dispersion-corrected density functional theory) and SQM-DH (dispersion and hydrogen bond-corrected semi-empirical quantum mechanical) perform much more accurately than older DFT and SQM approaches and also standard docking methods. In addition, DFT-D might soon become and SQM-DH already is fast enough to compute a large number of binding modes of comparably large protein/ligand complexes, thus allowing for a more accurate assessment of entropic effects.

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“…Fragmentation of molecular systems serves as a basis for defining properties of fragments and interactions between them, and for reducing the computational cost. Many fragmentation approaches have been developed …”

Section: Introductionmentioning

confidence: 99%

“…Many fragmentation approaches have been developed. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] In the fragment molecular orbital (FMO) method, [24][25][26][27][28] a molecular system is divided into fragments, also called monomers. Fragment calculations are performed in the electrostatic field obtained from the density of all fragments.…”

Section: Introductionmentioning

confidence: 99%

Multithreaded parallelization of the energy and analytic gradient in the fragment molecular orbital method

Mironov

Alexeev

Fedorov

2019

Int J of Quantum Chemistry

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The fragment molecular orbital method in GAMESS is parallelized in a multithreaded OpenMP implementation combined with the MPI version of the two‐level generalized distributed data interface. The energy and analytic gradient in gas phase and the polarizable continuum model of solvation are parallelized in this hybrid three‐level scheme, achieving a large memory footprint reduction and a high parallel efficiency on Intel Xeon Phi processors. The parallel efficiency is demonstrated on the Stampede2 and Theta supercomputers using up to 2048 nodes (262 144 threads).

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Calculation of protein–ligand binding affinities based on a fragment quantum mechanical method

Abstract: An efficient fragment-based quantum mechanical method has been successfully applied for reliable prediction of protein–ligand binding affinities.

Cited by 52 publications

References 75 publications

An Ab Initio QM/MM Study of the Electrostatic Contribution to Catalysis in the Active Site of Ketosteroid Isomerase

An Ab Initio QM/MM Study of the Electrostatic Contribution to Catalysis in the Active Site of Ketosteroid Isomerase

Recent Progress in Treating Protein–Ligand Interactions with Quantum-Mechanical Methods

Multithreaded parallelization of the energy and analytic gradient in the fragment molecular orbital method

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