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 coupled along with a highly simplified functional which lacks even the most rudimentary interactions captured in modern functionals.
Therefore, metal centers, covalently bound species, fragments, 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 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).
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.
Lance M Westerhoff
QuantumBio Inc.
REFERENCES:
1. Examples and additional information: http://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, pages
1233-1247.
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/
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 coupled along with a highly simplified functional which lacks even the most rudimentary interactions captured in modern functionals.
Therefore, metal centers, covalently bound species, fragments, 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 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).
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.
Dr. Lance M. Westerhoff is a co-founder and the President and General Manager of QuantumBio Inc - a high performance, computational chemistry software company based in State College, PA USA. Lance received a B.S. in Biochemistry and Applied Computer Science from Lebanon Valley College in 1998, and he went on to earn a M.S. and a Ph.D. in Chemistry from the Pennsylvania State University (PSU) in 2005 and 2006, respectively. While at PSU, he worked under the tutelage of Dr. Kenneth M. Merz, Jr. to study the relationships between protein structure and function utilizing linear scaling, semiempirical quantum mechanical (SE-QM) methodologies. In 2001/2002, Lance worked with Dr. Merz and Mr. Walter Greenblatt to start QuantumBio. Since that time, he has managed QuantumBio’s research and development group, has helped to raise investment funding, and has served as principle investigator and co-principle investigator on Small Business Innovative Research (SBIR)-style grants from the National Institutes of Health (NIH) and the Department of Defense (DoD). This work has lead in the development of several key applications of this SE-QM technology including a patented scoring function (QMScore), a nuclear magnetic resonance (NMR) structure scoring method (NMRScore), and most recently an X-ray refinement plugin to the Phenix crystallographic package. Along with these duties, he has played an active role in the business development and the strategic initiatives currently underway within QuantumBio.