PrimeX: A comprehensive package for accurate protein crystal structure refinement

PrimeX uses the OPLS-AA force field along with state-of-the-art technologies to refine protein crystal structures for computational drug discovery

The Advantage of X-ray Crystal Structure Refinement

The prevailing geometric restraints employed in protein crystallography apply experimental bond length and angle terms as well as other restraint terms that have been subsequently added. However, some potential issues arise when refined structures are used in downstream computational modeling.

Two key characteristics of protein crystal structures that could affect the accuracy of subsequent structure-based modeling are:

• High-energy contacts interfere with computational chemistry calculations, and are often removed by the application of restrained energy minimization to the crystal structure; the danger with this procedure is the introduction of changes in the structure not supported by the X-ray data.
• Most protein crystal structures at typical resolutions do not include hydrogens in the model, which must be added after the end of refinement for many molecular mechanics calculations.

Traditionally, attempts to remediate the aforementioned issues are done after refinement, which shifts the control of structural results away from the scientists who are most familiar with the interpretation of diffraction experiments. PrimeX directly addresses these concerns by restraining protein geometry to OPLS-AA (one of the most accurate and widely-deployed force fields for studying protein/ligand systems) during X-ray refinement, and by adding hydrogens during refinement and fully accounting for their existence in all energy computations.

Furthermore, just as the inclusion of hydrogen atoms provides important information for structure validation of refinement results, PrimeX also features improved accounting of non-bonded interactions during refinement, which are central to understanding ligand binding. Thus, PrimeX provides a complete environment that facilitates refinement and produces accurate structures more compatible with computational chemistry applications than those produced by other protein refinement programs.