Generalized dead-end elimination algorithms make large-scale protein side-chain structure prediction tractable: implications for protein design and structural genomics.
The dead-end elimination (DEE) theorems are powerful tools for the combinatorial optimization of protein side-chain placement in protein design and homology modeling. In order to reach their full potential, the theorems must be extended to handle very hard problems. We present a suite of new algorithms within the DEE paradigm that significantly extend its range of convergence and reduce run time. As a demonstration, we show that a total protein design problem of 10(115) combinations, a hydrophobic core design problem of 10(244) combinations, and a side-chain placement problem of 10(1044) combinations are solved in less than two weeks, a day and a half, and an hour of CPU time, respectively. This extends the range of the method by approximately 53, 144 and 851 log-units, respectively, using modest computational resources. Small to average-sized protein domains can now be designed automatically, and side-chain placement calculations can be solved for nearly all sizes of proteins and protein complexes in the growing field of structural genomics.
Department of Biochemistry, Duke University Medical Center, Box 3711, Durham, NC 27710, USA.
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Hellinga
D000465:Algorithms; D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins; D005353:Fibronectins / Q000737:chemistry / Q000235:genetics; D016678:Genome; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000235:genetics; D008956:Models, Chemical; D011487:Protein Conformation; D015202:Protein Engineering; D017510:Protein Folding; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; D014961:X-Ray Diffraction
D004268:DNA-Binding Proteins; D005353:Fibronectins; D007140:Immunoglobulin Fab Fragments; D012097:Repressor Proteins; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C016649:phage repressor proteins