Toward High-Resolution de Novo Structure Prediction for Small Proteins
10.1126/science.1113801
Crossref journal-article
American Association for the Advancement of Science (AAAS)
Science (221)
Abstract

The prediction of protein structure from amino acid sequence is a grand challenge of computational molecular biology. By using a combination of improved low- and high-resolution conformational sampling methods, improved atomically detailed potential functions that capture the jigsaw puzzle–like packing of protein cores, and high-performance computing, high-resolution structure prediction (<1.5 angstroms) can be achieved for small protein domains (<85 residues). The primary bottleneck to consistent high-resolution prediction appears to be conformational sampling.

Bibliography

Bradley, P., Misura, K. M. S., & Baker, D. (2005). Toward High-Resolution de Novo Structure Prediction for Small Proteins. Science, 309(5742), 1868–1871.

Authors 3
  1. Philip Bradley (first)
  2. Kira M. S. Misura (additional)
  3. David Baker (additional)
References 23 Referenced 721
  1. C. B. Anfinsen, E. Haber, M. Sela, F. H. White Jr., Proc. Natl. Acad. Sci. U.S.A.47, 1309 (1961). (10.1073/pnas.47.9.1309) / Proc. Natl. Acad. Sci. U.S.A. (1961)
  2. C. Levinthal, J. Chim. Phys.65, 44 (1968). (10.1051/jcp/1968650044) / J. Chim. Phys. (1968)
  3. J. Moult, K. Fidelis, A. Zemla, T. Hubbard, Proteins53 (Suppl 6), 334 (2003). (10.1002/prot.10556) / Proteins (2003)
  4. 10.1126/science.1089427
  5. J. Tsai et al., Proteins53, 76 (2003). (10.1002/prot.10454) / Proteins (2003)
  6. K. M. S. Misura, D. Baker, Proteins59, 15 (2005). (10.1002/prot.20376) / Proteins (2005)
  7. Z. Li, H. A. Scheraga, Proc. Natl. Acad. Sci. U.S.A.84, 6611 (1987). (10.1073/pnas.84.19.6611) / Proc. Natl. Acad. Sci. U.S.A. (1987)
  8. 10.1073/pnas.97.19.10383
  9. 10.1002/pro.5560060807
  10. Materials and methods are available as supporting material on Science Online.
  11. Inspection of the multiple sequence alignment revealed that the target sequence had several hydrophobic residues at exposed beta-sheet positions in this topology that were replaced by polar residues in other members of the alignment which offers a possible explanation for the absence of this topology in target-sequence models.
  12. C. A. Rohl, C. E. Strauss, D. Chivian, D. Baker, Proteins55, 656 (2004). (10.1002/prot.10629) / Proteins (2004)
  13. The single case where non-native models had lower energies than the native is a domain of a larger protein that has a quite hydrophobic interface and may not be stable in isolation.
  14. 10.1016/S0022-2836(03)00888-X
  15. J. J. Gray et al., J. Mol. Biol.331, 281 (2003). (10.1016/S0022-2836(03)00670-3) / J. Mol. Biol. (2003)
  16. C. Wang, O. Schueler-Furman, D. Baker, Protein Sci.14, 1328 (2005). (10.1110/ps.041222905) / Protein Sci. (2005)
  17. The physical chemistry of the packing of nonpolar atoms is considerably easier to model than the subtle trade-offs between desolvation of polar groups and the formation of buried polar interactions. Accurate modeling of functional sites may further require inclusion of explicit solvent molecules modeling of protonation states and interactions with ligands and polarizible electrostatics treatments. Together with the increase in the cost of refinement with chain length this has implications for structural genomics efforts: The refinement to high resolution of comparative models of large proteins (>400 amino acids) based on ∼30% sequence identity with many buried polar and charged residues may be a harder problem than the de novo prediction of the structures of small proteins.
  18. 10.1093/nar/28.1.235
  19. 10.1016/S0022-2836(05)80134-2
  20. To conserve computational resources no round 2 modeling was done for Glucose Permease IIBC because the native topology was never sampled during fragment assembly. Secondary structure predictions for all 50 homologs predicted an alpha helix in place of the N-terminal beta strand in the native structure.
  21. Core residues are defined as those with <20% solvent-accessible surface area compared with an extended G-X-G peptide.
  22. W. L. Delano (DeLano Scientific San Carlos CA USA 2002).
  23. We thank L. Malmström for computational assistance and K. Laidig for flawless administration of the computing resources necessary for these calculations. We gratefully acknowledge support from the Howard Hughes Medical Institute (P.B. and D.B.) and the Helen Hay Whitney Foundation (K.M.S.M.).
Dates
Type When
Created 19 years, 11 months ago (Sept. 15, 2005, 5:48 p.m.)
Deposited 1 year, 7 months ago (Jan. 9, 2024, 9:24 p.m.)
Indexed 3 weeks, 6 days ago (July 28, 2025, 2:36 a.m.)
Issued 19 years, 11 months ago (Sept. 16, 2005)
Published 19 years, 11 months ago (Sept. 16, 2005)
Published Print 19 years, 11 months ago (Sept. 16, 2005)
Funders 0

None

@article{Bradley_2005, title={Toward High-Resolution de Novo Structure Prediction for Small Proteins}, volume={309}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1113801}, DOI={10.1126/science.1113801}, number={5742}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Bradley, Philip and Misura, Kira M. S. and Baker, David}, year={2005}, month=sep, pages={1868–1871} }