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Computational design of proteins stereochemically optimized in size, stability, and folding speed
Author(s) -
Joshi Sadhna,
Rana Soumendra,
Wangikar Pramod,
Durani Susheel
Publication year - 2006
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.20537
Subject(s) - protein folding , topology (electrical circuits) , protein tertiary structure , folding (dsp implementation) , chemistry , protein secondary structure , protein design , sequence (biology) , protein structure prediction , molecular dynamics , simulated annealing , protein engineering , protein structure , crystallography , algorithm , computer science , computational chemistry , mathematics , combinatorics , engineering , mechanical engineering , biochemistry , enzyme
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. © 2006 Wiley Periodicals, Inc. Biopolymers 83: 122–134, 2006 This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com