Modeling protein-DNA interactions from sequences for small DNA-binding domains
Date Issued
2010
Date
2010
Author(s)
Chen, Ai-Mi
Abstract
Protein-DNA interaction plays an important role in many fundamental bio-chemical activities, for example, gene regulation and DNA repair. Researchers can understand how protein and DNA interact by examining available co-crystallized structures. However, such knowledge is very scarce because experimentally determining atom-level structure models of protein-DNA complexes requires expensive and time-consuming processes. On the contrary, due to recent advances in whole-genome sequencing technology, the sequence information of known DNA-binding proteins is much more than the number of protein-DNA tertiary complexes. Therefore, this study aims at constructing protein-DNA interaction models by integrating a number of in silico analyses based on sequences and predicted structures, i.e., creating the interaction models from sequences of proteins and DNA. This problem can be segmented into two sub-topics, both concerning tertiary structures: to predict protein tertiary structure in a systematic way and to construct predicted protein-DNA complexes. We use Rosetta to generate ten thousand decoys and select close-to-native protein structures from them. In addition, the protein-DNA complexes are predicted by the docking method, HADDOCK, or the template-based method, DBD2BS. Our results demonstrate that the protein structure can be predicted by de novo structure prediction for DNA-binding domains of small sizes. To be specific, after creating plenty of decoys by Rosetta, close-to-native structures can be selected by combination of correlation coefficient of sequence-based predicted RSA, decoy’s RSA, and one of knowledge-based energy scores. In addition, the performance of structural models created by de novo structure prediction is better than template-based modeling when only distant templates are available. All of the query proteins have prediction results of de novo structure prediction, while only proteins with templates which are similar to the query can be predicted by template-based methods. When both approaches deliver predictions, the qualities of modeling are similar. Furthermore, the accuracy of protein-DNA interacting models constructed by structure alignment is better than those predicted by docking tools when close-to-native protein structures are available. In summary, this study concludes that it is possible to construct the interaction model of protein and DNA even in the absence of co-crystallized structure.
Subjects
Protein-DNA interaction
protein structure prediction
de novo structure prediction
template-based modeling
solvent accessibility
decoy discrimination
Type
thesis
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