Event: Presentation: MidAtlantic Computational Chemists (MACC)

Title: High-­performance, quantum mechanics-­based macromolecular x-­ray refinement with Phenix/DivCon

Presenter: Lance M. Westerhoff, Ph.D.

Conference: Link (Powerpoint file available after conference)


Successful structure based drug discovery/design (SBDD) 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 rudimentary functional. Further, metal centers, covalently bound species, and so on 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 or ligand re-placement, with no guarantee that resulting models will continue to fit the experimental density. Our work has addressed this problem through the integration of DivCon6 – our linear scaling, semiempirical, quantum mechanics (SE-QM) implementation – with the popular Phenix x-ray crystallography platform. With Phenix/DivCon[1-3], SE-QM is used in “real-time” during each microcycle over the course of the refinement. With its inclusion of electrostatics, charge transfer, polarization, dispersion, hydrogen bonds, etcetera, this method is a much more rigorous, robust alternative to conventional stereochemical restraints and is able to accurately model experimental protein:ligand structures without “tweaking” restraints. At the same time, since the SE-QM method can be applied not only to the ligand but to the protein as well, the method will capture the influence of the surrounding structure on the ligand (and vise versa).

In addition to the method and its application, we will discuss PM6 refinement results for several key examples including structures with metal coordination spheres, covalent bonds, and other interesting protein:ligand chemistry situations. To date, we have used the method on hundreds of structures, and we have consistently found that QM refinement leads to ligand structures with much lower strain, and in some cases, the improvement is dramatic and as much 20+ fold.

  1. Examples and additional information: https://www.quantumbioinc.com/products/phenix-divcon/
  2. Borbulevych, O.Y., J.A. Plumley, R.M. Martin, K.M. Merz Jr, and L.M. Westerhoff, Accurate, macromolecular crystallographic refinement: Incorporation of the linear scaling, semiempirical quantum mechanics program DivCon into the Phenix refinement package. Acta Crystallogr D Biol Crystallogr, 2014. In Press.
  3. Borbulevych, O.Y., N.W. Moriarty, P.D. Adams, and L.M. Westerhoff, Quantum Mechanics-based Refinement in Phenix/DivCon. Computational Crystallography Newsletter, 2014. 5: p. 26-30. http://www.phenix-online.org/newsletter/