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High quality NMR structures: a new force field with implicit water and membrane solvation for Xplor-NIH

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Abstract

Structure determination of proteins by NMR is unique in its ability to measure restraints, very accurately, in environments and under conditions that closely mimic those encountered in vivo. For example, advances in solid-state NMR methods enable structure determination of membrane proteins in detergent-free lipid bilayers, and of large soluble proteins prepared by sedimentation, while parallel advances in solution NMR methods and optimization of detergent-free lipid nanodiscs are rapidly pushing the envelope of the size limit for both soluble and membrane proteins. These experimental advantages, however, are partially squandered during structure calculation, because the commonly used force fields are purely repulsive and neglect solvation, Van der Waals forces and electrostatic energy. Here we describe a new force field, and updated energy functions, for protein structure calculations with EEFx implicit solvation, electrostatics, and Van der Waals Lennard-Jones forces, in the widely used program Xplor-NIH. The new force field is based primarily on CHARMM22, facilitating calculations with a wider range of biomolecules. The new EEFx energy function has been rewritten to enable OpenMP parallelism, and optimized to enhance computation efficiency. It implements solvation, electrostatics, and Van der Waals energy terms together, thus ensuring more consistent and efficient computation of the complete nonbonded energy lists. Updates in the related python module allow detailed analysis of the interaction energies and associated parameters. The new force field and energy function work with both soluble proteins and membrane proteins, including those with cofactors or engineered tags, and are very effective in situations where there are sparse experimental restraints. Results obtained for NMR-restrained calculations with a set of five soluble proteins and five membrane proteins show that structures calculated with EEFx have significant improvements in accuracy, precision, and conformation, and that structure refinement can be obtained by short relaxation with EEFx to obtain improvements in these key metrics. These developments broaden the range of biomolecular structures that can be calculated with high fidelity from NMR restraints.

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Acknowledgements

We thank Vladimir Ladizhansky for helpful discussion. This research was supported by a grant from the National Institutes of Health (GM118186) and by the Resource for Molecular Imaging of Proteins at UCSD supported by the National Institutes of Health (P41 EB002031) and by the Intramural Research Program of the Center for Information Technology at the National Institutes of Health.

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  1. Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Ye Tian & Francesca M. Marassi

  2. Center for Information Technology, National Institutes of Health, Building 12A, Bethesda, MD, 20892-5624, USA

    Charles D. Schwieters

  3. Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0307, USA

    Stanley J. Opella

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  1. Ye Tian
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Correspondence to Francesca M. Marassi.

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Tian, Y., Schwieters, C.D., Opella, S.J. et al. High quality NMR structures: a new force field with implicit water and membrane solvation for Xplor-NIH. J Biomol NMR 67, 35–49 (2017). https://doi.org/10.1007/s10858-016-0082-5

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