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Int. J. Mol. Sci. 2016, 17(5), 612; doi:10.3390/ijms17050612

The Folding of de Novo Designed Protein DS119 via Molecular Dynamics Simulations

College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
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Author to whom correspondence should be addressed.
Academic Editor: Salvador Ventura
Received: 16 March 2016 / Revised: 13 April 2016 / Accepted: 13 April 2016 / Published: 26 April 2016
(This article belongs to the Collection Protein Folding)
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Abstract

As they are not subjected to natural selection process, de novo designed proteins usually fold in a manner different from natural proteins. Recently, a de novo designed mini-protein DS119, with a βαβ motif and 36 amino acids, has folded unusually slowly in experiments, and transient dimers have been detected in the folding process. Here, by means of all-atom replica exchange molecular dynamics (REMD) simulations, several comparably stable intermediate states were observed on the folding free-energy landscape of DS119. Conventional molecular dynamics (CMD) simulations showed that when two unfolded DS119 proteins bound together, most binding sites of dimeric aggregates were located at the N-terminal segment, especially residues 5–10, which were supposed to form β-sheet with its own C-terminal segment. Furthermore, a large percentage of individual proteins in the dimeric aggregates adopted conformations similar to those in the intermediate states observed in REMD simulations. These results indicate that, during the folding process, DS119 can easily become trapped in intermediate states. Then, with diffusion, a transient dimer would be formed and stabilized with the binding interface located at N-terminals. This means that it could not quickly fold to the native structure. The complicated folding manner of DS119 implies the important influence of natural selection on protein-folding kinetics, and more improvement should be achieved in rational protein design. View Full-Text
Keywords: protein folding; DS119; molecular dynamics simulation; transient dimer; intermediate states protein folding; DS119; molecular dynamics simulation; transient dimer; intermediate states
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Wang, M.; Hu, J.; Zhang, Z. The Folding of de Novo Designed Protein DS119 via Molecular Dynamics Simulations. Int. J. Mol. Sci. 2016, 17, 612.

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