Lukac, I, Abdelhakim, H, Ward, RA, St-Gallay, SA, Madden, JC and Leach, AG (2019) Predicting protein–ligand binding affinity and correcting crystal structures with quantum mechanical calculations: lactate dehydrogenase A. Chemical Science, 10 (7). pp. 2218-2227. ISSN 2041-6520

Preview

Text c8sc04564j.pdf - Published Version Available under License Creative Commons Attribution. Download (1MB) | Preview

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.

Item Type:	Article
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Divisions:	Pharmacy & Biomolecular Sciences
Publisher:	Royal Society of Chemistry (RSC)
Date Deposited:	21 Feb 2019 09:08
Last Modified:	04 Sep 2021 01:58
DOI or ID number:	10.1039/c8sc04564j
URI:	https://researchonline.ljmu.ac.uk/id/eprint/10190

View Item