Effect of single-point sequence alterations on the aggregationpropensity of a model protein Page: 2 of 27
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Abnormal protein aggregation, resulting in insoluble, biologically inactive agglomerates,
represents a serious problem in production, formulation, processing and storage of protein
drugs. In vivo, the occurrence of ordered fibrillar aggregates is associated with several
debilitating diseases including Alzheimer's and Parkinson's disease, Bovine Spongiform
Encephalopathy (BSE) (mad cow disease), Creutzfeldt-Jacob's disease, and amyotrophic lateral
sclerosis (ALS)2. Biotechnological concerns and efforts toward prevention or cure of
neurodegenerative diseases continue to motivate extensive experimental and computational
research aimed at identifying system properties that can be tuneded to suppress or control
aggregation. These properties include solvent composition3, presence of molecular chaperones or
aggregation inhibitors4, as well as mutations- affecting protein ability to aggregate67. Two classes
of mutations are of potential interest. In biotechnology and biomedical research, emphasis is on
minimally intrusive substitutions that can prevent or slow aggregation while preserving the
function of the protein. In materials science, on the other hand, there is emerging interest in
designing novel nanomaterials comprising, or templated by, fibrillar protein aggregates.
Laboratory screening of a large number of protein variants is, however, very expensive and time
consuming. Computer-assisted screening of potential mutations may significantly reduce the
number of experimental sequences to be examined.
While state-of-the-art modeling techniques do not suffice for full-atom simulations of
multi-chain protein systems on a practically relevant time scale, coarse-grained protein models
have provided useful insights into aggregation mechanisms and can suggest guidelines to control
the aggregation propensity of a protein12-38 Studies of aggregating proteins with Go residue
potentials highlighted strong correlations between binding states of adjacent protein residues'.
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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/m1/2/: accessed December 12, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.