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Computational design of proteins stereochemically optimized in size, stability, and folding speed

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Title Computational design of proteins stereochemically optimized in size, stability, and folding speed
 
Creator JOSHI, S
RANA, S
WANGIKAR, P
DURANI, S
 
Subject dead-end elimination
alpha-helical protein
beta-hairpin
energy landscape
aqueous-solution
3-helix bundle
peptide
kinetics
model
limit
de novo protein design
stereochemical engineering
triple helix bundle
barrier-less folding
transition state mimics
 
Description Artificial proteins potentially barrier free in the folding kinetics are approached computationally under the guidance of protein folding theories. The smallest and fastest folding globular protein triple-helix-bundle (THB) is so modified as to minimize or eliminate its presumed barriers in folding speed. As the barriers may reside in the ordering of either secondary or tertiary structure, the elements of both secondary and tertiary structure in the protein are targeted for prenucleation with suitable stereochemically constrained amino acid residues. The required elements of topology and sequence for the THB are optimized independently; first the topology is optimized with simulated annealing in polypeptides of highly simplified alphabet; next, the sequence in side chains is optimized using the standard inverse design methods. The resultant three best-adapted THBs, variable in topology and distinctive in sequences, are assessed by comparing them with a few benchmark proteins. The results of mainly molecular dynamics (MD) comparisons, undertaken in explicit water at different temperatures, show that the designed sequences are favorably placed against the chosen benchmarks as THB proteins potentially thermostable in the native folds. Folding simulation experiments with MD establish that the designed sequences are rapid in the folding of individual helices, but not in the evolution of tertiary structure; energetic cum topological frustrations remain but could be the artifacts of the starting conformations that were chosen in the THBs in the folding simulations. Overall, a practical high-throughput approach for de novo protein design has been developed that may have fruitful application for any type of tertiary structure. (c) 2006 .
 
Publisher JOHN WILEY & SONS INC
 
Date 2011-08-04T12:25:41Z
2011-12-26T12:54:43Z
2011-12-27T05:42:56Z
2011-08-04T12:25:41Z
2011-12-26T12:54:43Z
2011-12-27T05:42:56Z
2006
 
Type Article
 
Identifier BIOPOLYMERS, 83(2), 122-134
0006-3525
http://dx.doi.org/10.1002/bip.20537
http://dspace.library.iitb.ac.in/xmlui/handle/10054/9359
http://hdl.handle.net/10054/9359
 
Language en