We request a renewal of support for five years for our program project on New Methods for Biomolecular Structure Determination with component projects: (I) Direct Methods of Phase Determination, (II) New Algorithms for Intractable Direct Methods Problems, (III) Direct Methods phasing in Electron Crystallography, and (IV) Experimental Measurements for Direct Methods. Our work over the past four years has emphasized theoretical formulations and algorithmic developments to exploit modern computing technology to overcome the crystallographic phase problem. To date we have developed routinely applicable methods that yield ab initio the crystal structures of small proteins (approximately 500 independent non-hydrogen atoms) if they form crystals that provide diffraction data to atomic resolution (approximately 1 Angstrom). We seek renewed support to develop methods effective with larger structures and data of more limited resolution. Our plan is to develop more powerful methods by merging probabilistic direct methods and protein crystallographic techniques, viz. SIR (single isomorphous replacement), MIR (multiple isomorphous replacement), MR (molecular replacement), SAS (single-wavelength anomalous scattering), and MAD (multi-wavelength anomalous dispersion) techniques. The merger of these structure-based """"""""indirect"""""""" methods and mathematical direct methods will strengthen both, and the whole will be greater than the sum of its parts. The theoretical work on new methods will be complemented by a major new experimental effort in collaboration with the MacCHESS laboratory for biological synchrotron crystallography, where development of new methods based on optimized anomalous dispersion measurements will receive special emphasis.
| Xu, Hongliang; Hauptman, Herbert A (2004) Statistical approach to the phase problem. Acta Crystallogr A 60:153-7 |
| Shen, Qun (2003) Improving triplet-phase accuracy by symmetry observations in reference-beam diffraction measurements. Acta Crystallogr A 59:335-40 |
| Hauptman, Herbert A; Langs, David A (2003) The phase problem in neutron crystallography. Acta Crystallogr A 59:250-4 |
| Shen, Qun; Wang, Jun (2003) Recursive direct phasing with reference-beam diffraction. Acta Crystallogr D Biol Crystallogr 59:809-14 |
| Xu, Hongliang; Hauptman, Herbert A (2003) On integrating the techniques of direct methods and SIRAS: the probabilistic theory of doublets and its applications. Acta Crystallogr A 59:60-5 |
| Weeks, Charles M; Adams, Paul D; Berendzen, Joel et al. (2003) Automatic solution of heavy-atom substructures. Methods Enzymol 374:37-83 |
| Shen, Qun; Wang, Jun; Ealick, Steven E (2003) Anomalous difference signal in protein crystals. Acta Crystallogr A 59:371-3 |
| Lemke, Christopher T; Smith, G David; Howell, P Lynne (2002) S-SAD, Se-SAD and S/Se-SIRAS using Cu Kalpha radiation: why wait for synchrotron time? Acta Crystallogr D Biol Crystallogr 58:2096-101 |
| Xu, Hongliang; Hauptman, Herbert A; Weeks, Charles M (2002) Sine-enhanced Shake-and-Bake: the theoretical basis and applications to Se-atom substructures. Acta Crystallogr D Biol Crystallogr 58:90-6 |
| Hauptman, Herbert A; Guo, D Y; Xu, Hongliang et al. (2002) Algebraic direct methods for few-atoms structure models. Acta Crystallogr A 58:361-9 |
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