Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 5, Pages 1409-1414Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0808323106
Keywords
de novo protein structure prediction; ROSETTA
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Funding
- Howard Hughes Medical Institute
- National Institutes of Health
- European Union 6th Framework Program Rosetta-Membrane Project [MOIF-CT-2006-40496]
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Reliable structure-prediction methods for membrane proteins are important because the experimental determination of high-resolution membrane protein structures remains very difficult, especially for eukaryotic proteins. However, membrane proteins are typically longer than 200 aa and represent a formidable challenge for structure prediction. We have developed a method for predicting the structures of large membrane proteins by constraining helix-helix packing arrangements at particular positions predicted from sequence or identified by experiments. We tested the method on 12 membrane proteins of diverse topologies and functions with lengths ranging between 190 and 300 residues. Enforcing a single constraint during the folding simulations enriched the population of near-native models for 9 proteins. In 4 of the cases in which the constraint was predicted from the sequence, 1 of the 5 lowest energy models was superimposable within 4 angstrom on the native structure. Near-native structures could also be selected for heme-binding and pore-forming domains from simulations in which pairs of conserved histidine-chelating hemes and one experimentally determined salt bridge were constrained, respectively. These results suggest that models within 4 angstrom of the native structure can be achieved for complex membrane proteins if even limited information on residue-residue interactions can be obtained from protein structure databases or experiments.
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