Abstract
Quantum refinement has repeatedly been shown to be a powerful approach to interpret and improve macromolecular crystal structures, allowing for the discrimination between different interpretations of the structure, regarding the protonation states or the nature of bound ligands, for example. In this method, the empirical restraints, used to supplement the crystallographic raw data in standard crystallographic refinement, are replaced by more accurate quantum mechanical (QM) calculations for a small, but interesting, part of the structure. Previous studies have shown that the results of quantum refinement can be improved if the charge of the QM system is reduced by adding neutralizing groups. However, this significantly increases the computation time for the refinement. In this study, we show that a similar improvement can be obtained if the original highly charged QM system is instead immersed in a continuum solvent in the QM calculations. The best results are typically obtained with a high dielectric constant (ɛ). The continuum solvent improves real-space Z values, electron-density difference maps and strain energies, and it normally does not affect the discriminatory power of the calculations between different chemical interpretations of the structure. However, for structures with a low charge in the QM system or with a low crystallographic resolution (>2 Å), no improvement of the structures is seen.
Highlights
X-ray crystallography is the prime method for obtaining threedimensional structures of proteins
We investigate whether the results of quantum refinement can be improved by carrying out the quantum mechanical (QM) calculations in a conductor-like screening model (COSMO) continuum solvent (Klamt & Schuurmann, 1993) and whether the solvent may allow calculations with a smaller but more highly charged QM system
We test the approach for five different crystal structures to investigate when it is applicable, what is a proper choice of the dielectric Ryde, 2020), performing two separate QM calculations for the constant and whether it affects the discriminatory power of two alternative conformations
Summary
X-ray crystallography is the prime method for obtaining threedimensional structures of proteins. Standard crystallographic refinement optimizes an energy function of the form: Ecryst 1⁄4 wAEX-ray þ EMM ð1Þ where EX-ray is a crystallographic goodness-of-fit criterion, reflecting how well the current model (coordinates, occupancies and atomic displacement parameters), reproduce the experimental data, EMM is the empirical restraints and wA is a weight factor determining the relative importance of the two terms. This shows that protein crystal structures to a significant degree are computational and that they depend on the accuracy of the empirical restraints
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