Impact of Advances in Computing and Communications Technologies on Chemical Science and Technology Report of a Workshop (1999) / Chapter Skim
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4 The Role of Computational Biology in the Genomics Revolution
4 The Role of Computational Biology in the Genomics Revolution
Pages 44-61
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From page 44... ...
The most effective method for sifting out useful proteins from these genomic databases is the computer prediction of protein function. However, current methods, which are mainly sequence-based, are limited by the extent of similarity between sequences of unknown and known function; they increasingly fail as the sequence identity diverges into and beyond the twilight zone of sequence identity.
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From page 45... ...
Recent results indicate that for small proteins (those less than 100 residues) , ah initio folding approaches can predict structures at a level of quality (4- to 6-\ coordinate root mean square deviation for the backbone atoms)
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From page 46... ...
Then, predicted secondary structure restraints are obtained from a standard secondary structure prediction scheme (Ross and Sander, 1993; Rost, Schneider et al., 1993) supplemented by our LINKER algorithm (Kolinski, Skolnick et al., 1997)
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From page 47... ...
matches the native fold rather than the lowest average energy structure, this is also considered to be a partial success. Otherwise, by this rigorous criterion, the prediction is unsuccessful.
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From page 48... ...
It is very important to emphasize that all predictions use the identical parameter set and folding protocol. Table 4.2 shows the accuracy of the predicted secondary structure and tertiary contacts, as well as the results from the folding simulations.
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From page 49... ...
In particular, does one need a protein structure to predict protein function or is sequence information sufficient? If a protein's tertiary structure is needed, how close does it have to be to the native state to permit the protein's function to be identified?
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mrsW is the number of restraints satisfied in the alternative topology. nRelationship of lowest average energy structure to the native conformation if known.
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is the predicted (observed) secondary structure from PHD and LINKER.
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From page 52... ...
For example, the mammalian and bacterial serine proteases demonstrate that proteins with very similar functions can have very different three-dimensional structures (Brander and Tooze, 1991~. The geometry of the active site would not be recognized by local sequence signatures or by overall comparison of global tertiary structures, but only from an analysis of the structure of the functional residues around the active site.
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From page 53... ...
In fact, proteins function because of the arrangement of specific residues in three-dimensional space. The residues involved in protein function, particularly those at enzyme active sites, will be highly conserved throughout evolution.
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There are several distinct advantages to using geometric and conformational descriptors rather than local sequence signatures to describe protein function. It permits classification of proteins into families, even if there is little or no sequence identity to other proteins in the database.
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From page 55... ...
These results are summarized in Table 4.4. The method distinguishes protein pairs with similar active sites from protein pairs that are just topological cousins, i.e., those having similar global folds, but not necessarily similar active sites.
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From page 56... ...
cold ORF to the sequences of the lego, ldsb, chain A, and 2trx, chain A proteins using the BLAST search protocol, followed by analysis of the resulting sequence-sequence alignment for the active site residues specified by the thiol-disulfide oxidoreductase activity of the glutaredoxin/thioredoxin family. Results reported here are for a combination of the gapped-BLAST protocol and the PSI-BLAST alignment protocols.
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From page 57... ...
To accomplish this goal, in general, will require the development of more efficient conformational sampling algorithms as well as better potentials that can discriminate the native conformation from the myriad of alternative structures. In the area of structural genomics, where the objective is to determine the structure of all possible types of protein folds (Holm and Sander, 1996)
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From page 58... ...
SUMMARY These studies demonstrate that protein function prediction based on the sequence-to-structure-tofunction paradigm can successfully compete with more standard sequence-based approaches and may well identify the function of additional proteins in the twilight zone of sequence identity. What is very encouraging is that low-resolution structures as provided by state-of-the-art tertiary structure predictions can identify active sites by using appropriate three-dimensional conformational descriptors, the fuzzy functional forms.
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From page 59... ...
Identifying the tertiary fold of small proteins with different topologies from sequence and secondary structure using the genetic algorithm and extended criteria specific for strand regions.
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From page 60... ...
. Tertiary structure prediction of the KiX domain of CBP using Monte Carlo simulations driven by restraints derived from multiple sequence alignments.
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From page 61... ...
My guess is the next thing we are going to do is membrane protein tertiary structure prediction, and there there are some encouraging results.
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