Significant reduction in errors associated with nonbonded contacts in protein crystal structures: automated all-atom refinement with PrimeX.

Jeffrey A Bell,Ramy Farid,Kenneth L Ho

doi:10.1107/s0907444912017453

Jeffrey A Bell, Ramy Farid + Show 1 more

Open Access

https://doi.org/10.1107/s0907444912017453

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Abstract

All-atom models are essential for many applications in molecular modeling and computational chemistry. Nonbonded atomic contacts much closer than the sum of the van der Waals radii of the two atoms (clashes) are commonly observed in such models derived from protein crystal structures. A set of 94 recently deposited protein structures in the resolution range 1.5-2.8 Å were analyzed for clashes by the addition of all H atoms to the models followed by optimization and energy minimization of the positions of just these H atoms. The results were compared with the same set of structures after automated all-atom refinement with PrimeX and with nonbonded contacts in protein crystal structures at a resolution equal to or better than 0.9 Å. The additional PrimeX refinement produced structures with reasonable summary geometric statistics and similar R(free) values to the original structures. The frequency of clashes at less than 0.8 times the sum of van der Waals radii was reduced over fourfold compared with that found in the original structures, to a level approaching that found in the ultrahigh-resolution structures. Moreover, severe clashes at less than or equal to 0.7 times the sum of atomic radii were reduced 15-fold. All-atom refinement with PrimeX produced improved crystal structure models with respect to nonbonded contacts and yielded changes in structural details that dramatically impacted on the interpretation of some protein-ligand interactions.

Highlights

The majority of protein crystal structures are solved in the resolution range 1.7–2.8 A, a resolution range in which the diffraction experiment does not present sufficient information to accurately place individual atoms without additional chemical information
Before exploring the close contacts and structural geometry at moderate resolution, some perspective can be obtained on summary geometric statistics and the occurrence of clashes from ultrahigh-resolution protein structures
This study documents the existence of numerous unnecessary close contacts, including many severe ones, implicit in unitedatom models deposited in the PDB

Summary

Introduction

The majority of protein crystal structures are solved in the resolution range 1.7–2.8 A , a resolution range in which the diffraction experiment does not present sufficient information to accurately place individual atoms without additional chemical information. Electron-density peaks for H atoms are not observed in this resolution range owing to a low signal-to-noise ratio. H atoms are usually not explicitly included in molecular models of protein crystal structures. A molecular model without explicit coordinates for H atoms is denoted as an united-atom model, in contrast to an all-atom model. United-atom models are frequently insufficient for molecular modeling and computational chemistry applications (such as structure-based virtual screening or lead optimization). How is the gap bridged between current best crystallographic practices and the requirements of these other disciplines for all-atom structures that include hydrogen coordinates?

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