Binding affinities by alchemical perturbation using QM/MM with a large QM system and polarizable MM model.

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Abstract

The most general way to improve the accuracy of binding-affinity calculations for protein-ligand systems is to use quantum-mechanical (QM) methods together with rigorous alchemical-perturbation (AP) methods. We explore this approach by calculating the relative binding free energy of two synthetic disaccharides binding to galectin-3 at a reasonably high QM level (dispersion-corrected density functional theory with a triple-zeta basis set) and with a sufficiently large QM system to include all short-range interactions with the ligand (744-748 atoms). The rest of the protein is treated as a collection of atomic multipoles (up to quadrupoles) and polarizabilities. Several methods for evaluating the binding free energy from the 3600 QM calculations are investigated in terms of stability and accuracy. In particular, methods using QM calculations only at the endpoints of the transformation are compared with the recently proposed non-Boltzmann Bennett acceptance ratio (NBB) method that uses QM calculations at several stages of the transformation. Unfortunately, none of the rigorous approaches give sufficient statistical precision. However, a novel approximate method, involving the direct use of QM energies in the Bennett acceptance ratio method, gives similar results as NBB but with better precision, ∼3 kJ/mol. The statistical error can be further reduced by performing a greater number of QM calculations. © 2015 Wiley Periodicals, Inc.

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  • Theoretical Chemistry
Original languageEnglish
Pages (from-to)2114-2124
JournalJournal of Computational Chemistry
Volume36
Issue number28
Publication statusPublished - 2015
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039), Biophysical Chemistry (LTH) (011001011)

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