Fragment Molecular Orbital based affinity prediction toward pyruvate dehydrogenase kinases: Insights into the charge transfer in hydrogen bond networks

The fragment molecular orbital (FMO) method is a fast quantum-mechanics method that divides systems into pieces of fragments and performs ab initio calculations. The method has been expected to improve the accuracy of describing protein-ligand interactions by incorporating electronic effects. In thi...

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Bibliographic Details
Published inChemical & pharmaceutical bulletin Vol. 71; no. 4; pp. c22-00866 - 306
Main Authors Akaki, Tatsuo, Nakamura, Shinya, Nishiwaki, Keiji, Nakanishi, Isao
Format Journal Article
LanguageEnglish
Published Japan The Pharmaceutical Society of Japan 01.04.2023
Japan Science and Technology Agency
Subjects
Affinity
Aspartic acid
Binding sites
Charge transfer
Chemical bonds
Computational chemistry
Continuum modeling
fragment molecular orbital
hydrogen bond networks
Hydrogen Bonding
Hydrogen bonds
implicit solvation
Kinases
Ligands
Mechanics (physics)
Molecular orbitals
Oxidoreductases
Pyruvates
Pyruvic acid
Quantum Theory
Solvation
implicit solvation
hydrogen bond network
charge transfer
fragment molecular orbital
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Summary:The fragment molecular orbital (FMO) method is a fast quantum-mechanics method that divides systems into pieces of fragments and performs ab initio calculations. The method has been expected to improve the accuracy of describing protein-ligand interactions by incorporating electronic effects. In this article, FMO calculation with solvation methods were applied to the affinity prediction at the ATP-binding site of PDHK4. As the ionized aspartic acid lies at the center and is involved in the complex hydrogen bond networks, this system has turned out to be a difficult target to describe by traditional molecular-mechanics method. In the FMO calculation with the polarizable continuum model (PCM) solvation method, a considerable amount of charge (-0.27e) was transferred from the ionized aspartate to the surrounding residues. We found that using FMO with the PCM solvation method was important to increase the correlation, and by incorporating the ligand deformation energy, the correlation was improved to R = 0.81 for whole twelve compounds and R= 0.91 without one outlier compound.
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content type line 23
ISSN:0009-2363
1347-5223
DOI:10.1248/cpb.c22-00866