Successful structure based drug discovery/design is dependent upon accurate protein:ligand structure determination and characterization. The most popular method to determine the experimental structure of a complex is with the use of x-ray crystallography. In conventional x-ray refinement, the geometry of the ligand within the active site is modeled according to the practitioner's beliefs as expressed in the form of stereochemical restraints provided by the ligand library or CIFile along with a simplified functional. Further, metal centers, covalently bound species, and other exotic cases can be particularly difficult to refine correctly without significant human intervention. Traditionally, these deficiencies often lead to 'post-refinement processing,' such as force field-based structure optimization, with no guarantee that resulting models will continue to fit the experimental density. Our work has addressed this problem through the integration of the DivCon6 linear-scaling, semiempirical, quantum mechanics (SE-QM) engine with the popular Phenix crystallography platform. When this 'plug-in' is installed, QM-based refinement is performed in 'real time' during each refinement step. SE-QM - with its inclusion of electrostatics, charge transfer, polarization, dispersion, hydrogen bonds, and so on - is a much more rigorous alternative to conventional stereochemical restraints. At the same time, since the SE-QM method can be applied not only to the ligand but to the protein, the method captures the influence of the surrounding structure on the ligand (and vise versa).Upon completion of each refinement, standard crystallographic metrics along with strain, binding affinity prediction, and key interaction characteristics are reported. In addition to the method and its application, we will discuss PM6 refinement results for several examples including structures with metal coordination spheres, covalent bonds, and other key protein:ligand chemistry situations. Special attention will be paid to the impact of advanced refinement methods on structures from famous benchmark sets such as Astex, Iridium, CSAR, and others.

Quantum mechanics-based macromolecular X-ray refinement: The impact of advanced refinement methods on our understanding of protein:ligand structure and function

248th National Meeting (2014)

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