Title: The impact of advanced, QM-based X-ray refinement methods on our understanding of protein:ligand structure and function

Presenter: Lance M. Westerhoff, Ph.D.

Conference: Chemical Computing Group Inc – User Group Meeting

Location: W Hotel, Montreal, Quebec

Download: available after conference

Abstract:

Successful structure based drug discovery is dependent upon accurate, protein:ligand structure determination and characterization. Often determining or “rescuing” key interactions, while filtering out less important interactions, is extremely important to lead design and optimization. In conventional x-ray refinement, the geometry of the ligand or fragment 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. These restraints are usually coupled with a highly simplified functional which lacks even the most rudimentary interactions captured in modern functionals. Therefore, metal centers, covalently bound species, fragments, protonation states and so on can be difficult to refine correctly without significant human intervention. Traditionally, these deficiencies often lead to “post-refinement processing,” such as force field-based structure optimization and docking, 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[1-3]. 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 or fragment(s) but to the protein, the method captures the influence of the surrounding structure on the ligand (and vise versa).

This QM-based refinement can be initiated with our plug-in to MOE, and the method is therefore accessible to crystallographers and computational chemists alike. Further, using MOE during the subsequent analysis, we are able to explore these protein:ligand interactions in detail, and visualize the impact of the improved refinement functional on our understanding of the entire active site. In addition to the method and its application, PM6 refinement results will be presented for several examples including structures with metal coordination spheres, covalent bonds, and other key protein:ligand chemistry situations.

1. Examples and additional information: https://www.quantumbioinc.com/products/phenix-divcon/
2. Borbulevych, O.Y., J.A. Plumley, R.I. 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. D70, 1233-1247. https://www.quantumbioinc.com/publications/show/10.1107-S1399004714002260
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/