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The competition between protein folding and aggregation: Off‐lattice minimalist model studies
Author(s) -
Cellmer Troy,
Bratko Dusan,
Prausnitz John M.,
Blanch Harvey
Publication year - 2004
Publication title -
biotechnology and bioengineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.136
H-Index - 189
eISSN - 1097-0290
pISSN - 0006-3592
DOI - 10.1002/bit.20302
Subject(s) - protein aggregation , protein folding , folding (dsp implementation) , computational biology , biological system , computer science , complement (music) , chemistry , biophysics , biology , mutant , biochemistry , complementation , gene , electrical engineering , engineering
Protein aggregation has been associated with a number of human diseases, and is a serious problem in the manufacture of recombinant proteins. Of particular interest to the biotechnology industry is deleterious aggregation that occurs during the refolding of proteins from inclusion bodies. As a complement to experimental efforts, computer simulations of multi‐chain systems have emerged as a powerful tool to investigate the competition between folding and aggregation. Here we report results from Langevin dynamics simulations of minimalist model proteins. Order parameters are developed to follow both folding and aggregation. By mapping natural units to real units, the simulations are shown to be carried out under experimentally relevant conditions. Data pertaining to the contacts formed during the association process show that multiple mechanisms for aggregation exist, but certain pathways are statistically preferred. Kinetic data show that there are multiple time scales for aggregation, although most association events take place at times much shorter than those required for folding. Last, we discuss results presented here as a basis for future work aimed at rational design of mutations to reduce aggregation propensity, as well as for development of small‐molecular weight refolding enhancers. © 2004 Wiley Periodicals, Inc.