Charles M. Weeks, Ph.D.
Senior Research Scientist, Hauptman-Woodward Inst.
Professor of Structural Biology, SUNY-Buffalo

EDUCATION
B.S. in Biochemistry, Cornell University, 1966
Ph.D. in Biophysics, SUNY Buffalo, 1970

My research interests lie in computational crystallography, especially the development of algorithms and software for automating the process of protein structure determination. Crystallographic study of a protein involves a mathematical analysis of X-ray diffraction data leading to the computation of electron-density maps and the building of molecular models.  One of the key steps in this process involves solution of the so-called crystallographic phase problem, and this step has been a focal point of my research.

In the crystallographic experiment, the radiation incident on a single crystal is scattered in many directions to form a distinctive diffraction pattern that is characteristic of the atomic arrangement within the crystal.  The intensities of the scattered X-rays can be measured when they strike a suitable electronic recorder.  However, X-rays are wavelike in nature, and their intensities vary with time.  In order to work backwards from the diffraction pattern to the molecular structure, it is necessary to know not only the intensity, but also the relative timing or phase when each wave hits the recording device. Our inability to measure the phase angles experimentally gives rise to the phase problem.   

Working with my colleagues Russ Miller and Herb Hauptman, I have developed a powerful algorithm, known as Shake-and-Bake, for analyzing diffraction data and recovering the phase information.  Using the Shake-and-Bake method, intermediate-sized molecular structures, including small proteins containing as many as 1,500 non-hydrogen atoms, can be solved successfully, and their three-dimensional structures can be visualized.  This represents a significant improvement over earlier methods that were limited, in most cases, to structures containing about 100 non-hydrogen atoms.  One of the first successes of our method (in collaboration with Patrick Loll of the University of Pennsylvania) was the long-sought structure of vancomycin, widely known as an antibiotic of last resort.  The Shake-and-Bake method can also be applied effectively to very large protein molecules containing many thousands of non-hydrogen atoms.  In such cases, it is used to locate a relatively small number of heavier atoms with special X-ray scattering properties.  These heavy atoms provide a substructure that can be used as a starting point for revealing the rest of the protein molecule.

We have implemented the Shake-and-Bake method is a computer program call SnB, and this program has been distributed to hundreds of crystallographic labs from our web site http://www.hwi.buffalo.edu/SnB/.  Recently, we have collaborated with Bill Furey at the University of Pittsburgh to provide a seamless interface, called BnP, between SnB and other crystallographic software.  This interface provides a coordinated control of several steps in the protein structure determination pathway, and it facilitates a high degree of automation.  Currently, we are preparing a version of BnP that will reduce the time required for computation and increase throughput by performing many of the necessary calculations in parallel on several processors.  This version will be adapted for running on a computational grid or network of computers.

SELECTED PUBLICATIONS
Dr. Weeks' publications include total of approximately 140 papers & chapters, 150 abstracts, and one book

• Weeks, C.M., Roszak, A.W., Erman, M., Kaiser, R., Jörnvall, H. & Ghosh, D. Crystal Structure of Rabbit Liver Fructose-1,6-Bisphosphatase at 2.3Å Resolution, Acta Cryst. D55, 93-102 (1999).
• Weeks, C.M. & Miller, R. Optimizing Shake-and-Bake for Proteins, Acta Cryst. D55, 492-500 (1999).
• Weeks, C.M. & Miller, R. The Design and Implementation of SnB v2.0, J. Appl. Cryst. 32, 120-124 (1999).
• Weeks, C.M., Xu, H., Hauptman, H.A., and Shen, Q., Shake-and-Bake Applications Using Simulated Reference-Beam Data for Crambin, Acta Cryst. A56, 280-283 (2000).
• Sheldrick, G. M., Hauptman, H. A., Weeks, C. M., Miller, R. & Usón, I. Chapter 16.1, Ab Initio Phasing. In International Tables of Macromolecular Crystallography, Vol. F, M. Rossman & E. Arnold (Eds.), pp. 333-351. Dordrecht: Kluwer Academic Publishers (2001).
• Weeks, C. M., Blessing, R. H., Miller, R., Mungee, R., Potter, S. A., Rappleye, J., Smith, G. D., Xu, H. & Furey, W. Towards automated protein structure determination: BnP, the SnB-PHASES interface, Z. Kristallogr. 217, 686-693 (2002).
• Weeks, C. M., Adams, P. D., Berendzen, J., Brünger, A. T., Dodson, E. J., Grosse-Kunstleve, R. W., Schneider, T. R., Sheldrick, G. M., Terwilliger, T. C., Turkenburg, M. & Usón, I. Automatic solution of heavy-atom substructures, Methods Enzymol. 374, 37-83 (2003).