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

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.

Xplor‐NIH for molecular structure determination from NMR and other data sources

“…This term includes van der Waals, electrostatic and solvent contributions. It can be used in concert with either TorsionDBPot or the standard XPLOR DIHE dihedral term using CHARMM22 parameters …”

Integrated NMR and cryo-EM atomic-resolution structure determination of a half-megadalton enzyme complex

“…The fit structure was used as initial coordinates for the first calculation, and the lowest energy calculated structure from each step was utilized as the initial structure for the subsequent calculation. Finally, the outcome of the calculation using the 4.1 Å map was refined in implicit solvent using the effective energy function for Xplor-NIH (EEFx) 50 . For generating the structures shown in Figure 4F and G, this gradual refinement process was stopped before adding the higher-resolution maps (i.e., before adding the 6 or 4.1 Å resolution maps, respectively), in order to evaluate the quality of the structures resolution from lower-resolution EM data.…”

Defining the mobility range of a hinge-type connection using molecular dynamics and metadynamics

“…The system was heated to 3500 K and cooled down in 12.5 K steps. Instead of the standard Xplor force field, the eefx2 implicit force field was chosen, since it displays higher accuracy and quality of the calculated structure in comparison to the native state [50]. The calculation was performed with 5000 structures while the 20 most stable conformations which showed a large resemblance to each other were extracted.…”