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Issue 7, 2019
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Predicting protein–ligand binding affinity and correcting crystal structures with quantum mechanical calculations: lactate dehydrogenase A

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Abstract

Accurately computing the geometry and energy of host–guest and protein–ligand interactions requires a physically accurate description of the forces in action. Quantum mechanics can provide this accuracy but the calculations can require a prohibitive quantity of computational resources. The size of the calculations can be reduced by including only the atoms of the receptor that are in close proximity to the ligand. We show that when combined with log P values for the ligand (which can be computed easily) this approach can significantly improve the agreement between computed and measured binding energies. When the approach is applied to lactate dehydrogenase A, it can make quantitative predictions about conformational, tautomeric and protonation state preferences as well as stereoselectivity and even identifies potential errors in structures deposited in the Protein Data Bank for this enzyme. By broadening the evidence base for these structures from only the diffraction data, more chemically realistic structures can be proposed.

Graphical abstract: Predicting protein–ligand binding affinity and correcting crystal structures with quantum mechanical calculations: lactate dehydrogenase A

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Publication details

The article was received on 12 Oct 2018, accepted on 19 Dec 2018 and first published on 04 Jan 2019


Article type: Edge Article
DOI: 10.1039/C8SC04564J
Citation: Chem. Sci., 2019,10, 2218-2227
  • Open access: Creative Commons BY license
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    Predicting protein–ligand binding affinity and correcting crystal structures with quantum mechanical calculations: lactate dehydrogenase A

    I. Lukac, H. Abdelhakim, R. A. Ward, S. A. St-Gallay, J. C. Madden and A. G. Leach, Chem. Sci., 2019, 10, 2218
    DOI: 10.1039/C8SC04564J

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