Refinamiento de estructuras macromoleculares cristalográficas


  • Pavel V. Afonine Lawrence Berkeley National Laboratory
  • Alexandre Urzhumtsev Centre for Integrative Biology, IGBMC, CNRS-INSERM-UdS. Université de Lorraine
  • Paul D. Adams Lawrence Berkeley National Laboratory. University of California Berkeley


Palabras clave:

cálculos rápidos de gradiente, constricciones, factores de estructura, mapas de Fourier, máxima verosimilitud, medio acuoso, minimización, neutrones, optimización, rayos-X, refinamiento, restricciones


El refinamiento es un paso clave en el proceso de determinación de una estructura cristalográfica al garantizar que la estructura atómica de la macromolécula final represente de la mejor manera posible los datos de difracción. Han hecho falta varias décadas para poder desarrollar nuevos métodos y herramientas computacionales dirigidas a dinamizar esta etapa. En este artículo ofrecemos un breve resumen de los principales hitos en la computación cristalográfica y de los nuevos métodos relevantes para el refinamiento de estructuras.


Los datos de descargas todavía no están disponibles.


Abagyan, R. A., Totrov, M. M. and Kuznetsov, D. A. (1994). ICM – a new method for protein modeling and design – Applications to docking and structure prediction from the distorted native conformation. Journal of Computational Chemistry, 15, pp. 488-506.

Adams, P. D., Mustyakimov, M., Afonine, P. V. and Langan, P. (2009). Generalized X-ray and neutron crystallographic analysis: more accurate and complete structures for biological macromolecules. Acta Crystallographica, D65, pp. 567-573. PMid:19465771 PMCid:PMC2685734

Adams, P. D., Pannu, N. S., Read, R. J. and Bru.nger, A. T. (1997). Cross-validated maximum likelihood enhances crystallographic simulated annealing refinement. Proceedings of National Academy of Science, 94, pp. 5018-5023.

Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L. -W., Kapral, G. J., Grosse-Kunstleve, R. W., McCoy, A. J., Moriarty, N. W., Oeffner, R., Read, R. J., Richardson, D. C., Richardson, J. S., Terwilliger, T. C. and Zwart, P. H. (2010). PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallographica, D66, pp. 213-221. PMid:20124702 PMCid:PMC2815670

Afonine, P., Lunin, V. Y. and Urzhumtsev, A. (2003). MLMF: least-squares approximation of likelihood-based refinement criteria. Journal of Applied Crystallography, 36, pp. 158-159.

Afonine, P. V., Grosse-Kunstleve, R. W., Adams, P. D., Lunin, V. Y. and Urzhumtsev, A. (2007). On macromolecular refinement at subatomic resolution with interatomic scatterers. Acta Crystallographica, D63, pp. 1194-1197. PMid:18007035 PMCid:PMC2808317

Afonine, P. V., Grosse-Kunstleve, R. W., Urzhumtsev, A. and Adams, P. D. (2009). Automatic multiple-zone rigid-body refinement with a large convergence radius. Journal of Applied Crystallography, 42, pp. 607-615. PMid:19649324 PMCid:PMC2712840

Afonine, P. V., Mustyakimov, M., Grosse-Kunstleve, R. W., Moriarty, N. W., Langan, P. and Adams, P. D. (2010). Joint X-ray and neutron refinement with phenix.refine. Acta Crystallographica, D66, pp. 1153-1163. PMid:21041930 PMCid:PMC2967420

Afonine, P. V., Grosse-Kunstleve, R. W., Echols, N., Headd, J. J., Moriarty, N. W.; Mustyakimov, M., Tenwilliger, T. C. Urzhumtsev, A. and Zwart, P. H. (2012). Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallographica, D68, pp. 352-367. PMid:22505256 PMCid:PMC3322595

Afonine, P. V., Grosse-Kunstleve, R. W., Adams, P. D. and Urzhumtsev, A. (2013). Bulk-solvent and overall scaling revisited: faster calculations, improved results. Acta Crystallographica, D69, pp. 625-634. PMid:23519671 PMCid:PMC3606040

Agarwal, R. C. (1978). A new least-squares refinement technique based on the fast Fourier transform algorithm. Acta Crystallographica, A34, pp. 791-809.

Agarwal, R. C. (1981). New results on fast Fourier least-squares refinement technique. In Machin, P. A., Campbell, J. W. and Elder, M. (comps.). Refinement of Protein Structures. Proceedings of the Daresbury Study Weekend, 15-16 November 1980. Daresbury, Warrington: Science and Engineering Research Council, Daresbury Laboratory, pp. 24-28.

Ambartsumian, V. A. (1929). On the Relationship between the Solution and the Resolvente of the Integral Equation of the Radiative Balance. Zeitschrift fu.r Physik, 52, pp. 263-267.

Baur, W. and Strassen, V. (1983). The complexity of partial derivatives. Theoretical Computer Science, 22, pp. 317-330.

Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N. and Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Research, 28, pp. 235-242. PMid:10592235 PMCid:PMC102472

Bernstein, F. C., Koetzle, T. F., Williams, G. J. B., Meyer, E. F., Brice, M. D., Rodgers, J. R., Kennard, O., Shimanouchi, T. and Tasumi, M. (1977). The Protein Data Bank: a computer- based archival file for macromolecular structures. Journal of Molecular Biology, 112, pp. 535-542.

Blanc, E., Roversi, P., Vonrhein, C., Flensburg, C., Lea, S. M. and Bricogne, G. (2004). Refinement of severely incomplete structures with maximum likelihood in BUSTER-TNT. Acta Crystallographica, D60, pp. 2210-2221. PMid:15572774

Booth, A. D. (1947). Application of the method of steepest descents to X-ray structure analysis. Nature, 160, p. 196.

Bricogne, G. and Irwin, J. (1996). Maximum likelihood structure refinement: theory and implementation within BUSTER + TNT. In Dodson, E. J., Moore, M., Ralph, A. and Bailey, S. (eds.). Macromolecular Refinement: Proceedings of the CCP4 Study Weekend. Daresbury, Warrington: Science and Engineering Research Council, Daresbury Laboratory, pp. 85-92.

Brünger, A. T., Kuriyan, J. and Karplus, M. (1987). Crystallographic R factor refinement by molecular dynamics. Science, 235, pp. 458- 460. PMid:17810339

Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse-Kunstleve, R. W., Jiang, J. S., Kuszewski, J., Nilqes, M., Pannu, N. S., Read, R. J., Rice, L. M., Somonson, T. and Warren, G. L. (1998). Crystallography and NMR system: a new software suite for macromolecular structure determination. Acta Crystallographica, D54, pp. 905-921.

Canfield, P., Dahlbom, M. G., Reimers, J. R. and Hush, N. S. (2006). Density-functional geometry optimization of the 150,000-atom photosystem-I trimer. Journal of Chemical Physics, 124, pp. 024301-024315. PMid:16422577

Chapman, M. (1995). Restrained real-space macromolecular atomic refinement using a new resolution-dependent electron- density function. Acta Crystallographica, A51, pp. 69-80.

Cochran, W. (1948). The Fourier method for crystal-structure analysis. Acta Crystallographica, 1, pp. 138-142.

Cooley, J. W. and Tukey, J. W. (1965). An algorithm for machine calculation of complex Fourier series. Mathematics of Computation, 19, pp. 297-301.

Diamond, R. (1971). A real-space refinement procedure for proteins. Acta Crystallographica, A27, pp. 436-452.

Dodson, E. J., Isaacs, N. W. and Rollett, J. S. (1976). A method for fitting satisfactory models to sets of atomic positions in protein structure refinements. Acta Crystallographica, A32, pp. 311-315.

Driessen, H., Haneef, M. I. J., Harris, G. W., Howlin, B., Khan, G. and Moss, D. S. (1989). TLSANL - TLS parameter-analysis program for segmented anisotropic refinement of macromolecular structrures. Journal of Applied Crystallography, 22, pp. 510-516.

Ewald, P. P. (1913). About the theory of the interference of X-rays in crystals (Zur Theorie der interferenzen der Röntgen-strahlen in kristallen). Physikalische Zeitschrift, 14, pp. 465–472.

Falköf, O., Collyer, C. A. and Reimers, J. R. (2012). Toward ab initio refinement of protein X-ray crystal structures: interpreting and correlating structural fluctuations. Theoretical Chemistry Accounts, 131, 1076.

Fenn, T. D., Schnieders, M. J. and Bru.nger, A. T. (2010). A smooth and differentiable bulk-solvent model for macromolecular diffraction. Acta Crystallographica, D66, pp. 1024–1031. PMid:20823553 PMCid:PMC2935282

Finzel, B. C. (1987). Incorporation of fast Fourier-transforms to speed restrained least-squares refinement of protein structures. Journal of Applied Crystallography, 20, pp. 53-55.

Freer, S. T., Alden, R. A., Carter, W. C. Jr. and Kraut, J. (1975). Crystallographic structure refinement of chromatium high potential iron protein at two Angstroms resolution. Journal of Biological Chemistry, 250, pp. 46-54.

Guillot, B., Viry, L., Guillot, R., Lecomte, C. and Jelsch., C. (2001). Refinement of proteins at subatomic resolution with MOPRO. Journal of Applied Crystallography, 34, pp. 214-223.

Haneef, I., Moss, D. S., Stanford, M. J. and Borkakoti, N. (1985). Restrained structure- factor least-squares refinement of protein structures using a vector processing computer. Acta Crystallographica, A41, pp. 426-433.

Hansen, N. K. and Coppens, P. (1978). Testing aspherical atom refinements on small-molecule data sets. Acta Crystallographica, A34, pp. 909-921.

Headd, J. J., Echols, N., Afonine, P. V., Grosse-Kunstleve, R. W., Chen, V. B., Moriarty, N. W.,Richardson, D. C., Richardson, J. S. and Adams, P. D. (2012). Use of knowledge-based restraints in phenix.refine to improve macromolecular refinement at low resolution. Acta Crystallographica, D68, pp. 381-390.

Headd, J. J., Echols, N., Afonine, P. V., Moriarty, N. W., Gildea, R. J. and Adams, P. D. (2014). Flexible torsion-angle noncrystallographic symmetry restraints for improved macromolecular structure refinement. Acta Crystallographica, D70, pp. 1346-1356. PMid:24816103 PMCid:PMC4014122

Hestenes, M. R. and Stiefel, E. (1952). Methods of conjugate gradients for solving linear systems. Journal of Research of the National Bureau of Standards, 49, pp. 409-436.

Hendrickson, W. A. and Konnert, J. H. (1980). In Srinivasan, R., Subramanian, E. and Yathindra, N. (eds.). Biomolecular Structure, Conformation, Function, and Evolution (vol. 1). New York: Pergamon, pp. 43-57.

Hughes, E. W. (1941). The crystal structure of melanine. Journal of the Amererican Chemical Society, 63, pp. 1737-1752.

Jack, A. and Levitt, M. (1978). Refinement of large structures by simultaneous minimization of energy and R factor. Acta Crystallographica, A34, pp. 931-935.

Jelsch., C., Guillot, B., Lagoutte, A. and Lecomte, C. (2005). Advances in protein and small-molecule charge-density refinement methods using MoPro. Journal of Applied Crystallography, 38, pp. 38-54.

Jiang, J.-S. and Bru.nger, A. T. (1994). Protein hydration observed by X-ray diffraction. Solvation properties of penicillopepsin and neuroaminidase crystal structures. Journal of Molecular Biology, 243, pp. 100-115.

Kalinin, D. I. (1980). Use of a cylindrical model of a protein to determine the spatial structure of the rhombic modification of leghaemoglobin. Soviet Physics. Crystallography, 25, pp. 307-313.

Kim, K. M., Nesterov, Yu. E. and Cherkassky, B. V. (1984). Ocenka trudoemkosti vyčislenija gradienta. Doklady Academii Nauk SSSR, 275, pp. 1306-1309.

Konnert, J. H. (1976). A restrained-parameter structure-factor least-squares refinement procedure for large asymmetric units. Acta Crystallographica, A32, pp. 614-617.

Konnert, J. H. and Hendrickson, W. A. (1980). A restrained-parameter thermal-factor refinement procedure. Acta Crystallographica, A36, pp. 344-350.

Lanczos, C. (1952). Solution of systems of linear equations by minimized iterations. Journal of Research of the National Bureau of Standards, 49, pp. 33-53.

Lunin, V. Y. and Urzhumtsev, A. (1983). Program construction for refinement of macromolecular atomic structures on the base of Fast Fourier transformation and Fast differentiation algorithms. Preprint, Pushchino, ONTI NCBI.

Lunin, V. Y. and Urzhumtsev, A. (1984). Improvement of protein phases by coarse model modification. Acta Crystallographica, A40, pp. 269-277.

Lunin, V. Y. and Urzhumtsev, A. (1985). Program construction for macromolecule atomic model refinement based on the fast Fourier transform and fast differentiation algorithms. Acta Crystallographica, A41, pp. 327-333.

Lunin, V. Y., Afonine, P. V. and Urzhumtsev, A. (2002). Likelihood-based refinement. I. Irremovable model errors. Acta Crystallographica, A58, pp. 270-282.

Murshudov, G. N., Vagin, A. A. and Dodson, E. J. (1997). Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallographica, D53, pp. 240-255. PMid:15299926

Pannu, N. S. and Read, R. J. (1996). Improved Structure Refinement Through Maximum Likelihood. Acta Crystallographica, A52, pp. 659-668.

Pannu, N. S., Murshudov, G. N., Dodson, E. J. and Read, R. J. (1998). Incorporation of Prior Phase Information Strengthens Maximum-Likelihood Structure Refinement. Acta Crystallographica, D54, pp. 1285–1294.

Reimers, J. R. (2011). Computational Methods for Large Systems: Electronic Structure Approaches for Biotechnology and Nanotechnology. Hoboken, New Jersey: Wiley.

Rice, L. M. and Brunger, A. T. (1994). Torsion angle dynamics: reduced variable conformational sampling enhances crystallographic structure refinement. Proteins: Structure, Function and and Genetics, 19, pp. 277-290. PMid:7984624

Runge, C. and König, D. (1924). Die Grundlehren der mathematischen Wissenschaften (vol. II). Berlin: Springer.

Sayre, D. (1951). The calculation of structure factors by Fourier summation. Acta Crystallographica, 4, pp. 362-367.

Scheringer, C. (1963). Least-squares refinement with the minimum number of parameters for structures containing rigid-body groups of atoms. Acta Crystallographica, 16, pp. 546-550.

Schnieders, M. J., Fenn, T. D., Pande, V. S. and Brunger, A. T. (2009). Polarizable atomic multipole X-ray refinement: application to peptide crystals. Acta Crystallographica, D65, pp. 952-965. PMid:19690373 PMCid:PMC2733883

Schomaker, V. and Trueblood, K. N. (1968). On rigid-body motion of molecules in crystals. Acta Crystallographica, B24, pp. 63-76.

Sheldrick, G. M. and Schneider, T. R. (1997). SHELXL: High-resolution refinement. Methods in Enzymology, 277B, pp. 319-343.

Steigemann, W. (1974). Ph.D. thesis, Technische Universitat, München.

Sussman, J. L., Holbrook, S. R., Church, G. M. and Kim, S.-H. (1977). Structure-factor least-squares refinement procedure for macromolecular structures using constrained and restrained parameters. Acta Crystallographica, A33, pp. 800-804.

Ten Eyck, L. F. (1973). Crystallographic fast Fourier transforms. Acta Crystallographica, A29, pp. 183-191.

Ten Eyck, L. F. (1977). Efficient structure-factor calculation for large molecules by the fast Fourier transform. Acta Crystallographica, A33, pp. 486-492.

Tronrud, D. E., Ten Eyck., L. F. and Matthews, B. W. (1987). An efficient general- purpose least-squares refinement program for macromolecular structures. Acta Crystallographica, A43, pp. 489-501.

Tronrund, D. E. (1992). Conjugate-direction minimization: an improved method of the refinement of macromolecules. Acta Crystallographica, A48, pp. 912-916.

Turk, D. (1992). PhD thesis. Technische Universität München, Germany.

Urzhumtsev, A. G., Lunin, V. Yu. and Vernoslova, E. A. (1989). FROG - high-speed restraint-constraint refinement program for macromolecular structure. Journal of Applied Crystallography, 22, pp. 500-506.

Watenpaugh, K. D., Sieker, L. C., Herriott, J. R. and Jensen, L. H. (1973). Refinement of model of a protein - rubredoxin at 1.5 Å resolution. Acta Crystallographica, B29, pp. 943-956.

Westhof, E., Dumas, Ph. and Moras, D. (1988). Restrained refinement of two crystalline forms of yeast aspartic acid and phenylalanine transfer RNA crystals. Acta Crystallographica, A44, pp. 112-123.



Cómo citar

Afonine, P. V., Urzhumtsev, A., & Adams, P. D. (2015). Refinamiento de estructuras macromoleculares cristalográficas. Arbor, 191(772), a219.