Effect of single-point sequence alterations on the aggregationpropensity of a model protein Page: 1 of 27
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Effect of single-point sequence alterations on the aggregation
propensity of a model protein
Dusan Bratko,2*, Troy Cellmer2, John M. Prausnitz23 and Harvey W. Blanch2
Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284
2Department of Chemical Engineering, University of California, Berkeley, CA 94720
3Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
September 16, 2005
Sequences of contemporary proteins are believed to have evolved through process
that optimized their overall fitness including their resistance to deleterious aggregation.
Biotechnological processing may expose therapeutic proteins to conditions that are much
more conducive to aggregation than those encountered in a cellular environment. An
important task of protein engineering is to identify alternative sequences that would
protect proteins when processed at high concentrations without altering their native
structure associated with specific biological function. Our computational studies exploit
parallel tempering simulations of coarse-grained model proteins to demonstrate that
isolated amino-acid residue substitutions can result in significant changes in the
aggregation resistance of the protein in a crowded environment while retaining protein
structure in isolation. A thermodynamic analysis of protein clusters subject to competing
processes of folding and association shows that moderate mutations can produce effects
similar to those caused by changes in system conditions, including temperature,
concentration, and solvent composition that affect the aggregation propensity. The range
of conditions where a protein can resist aggregation can therefore be tuned by sequence
alterations although the protein generally may retain its generic ability for aggregation.
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Bratko, Dusan; Cellmer, Troy; Prausnitz, John M. & Blanch, Harvey W. Effect of single-point sequence alterations on the aggregationpropensity of a model protein, article, October 7, 2005; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc877725/m1/1/: accessed December 18, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.