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A Novel Physico-Chemical Property Based Model for Studying the Effects of Mutation on the Aggregation of Peptides

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Abstract:

Macromolecular events like protein aggregation are complex processes involving physico-chemical properties of their constituting residues. In this study, we used 5-dimensional physico-chemical property (PCP-descriptors) descriptors of amino acids, derived from 237 physico-chemical properties, to develop linear (LM) and neural network (NM) based regression models. We demonstrate their prediction performance in log values of aggregation rates ( ψ ) for 15 human muscle acyl-phosphatase (AcP) mutants. The correlation coefficient between the predicted and the observed ψ - values of the point mutations by LM and NM was 0.81 (p-value<0.001) and 0.71 (p-value<0.002) respectively. Using LM, we calculated ψ -values for all possible mutations and performed an average linkage cluster analysis. We identified three groups of amino acids that differ in tolerance to mutations, resulting in increased or decreased aggregation rates. We suggest that our linear regression model can be applied to predict the aggregation propensity of point mutants where only sequence information is known. We also show that sequences containing beta-sheet classes of Structural Classification of Proteins (SCOP) have a higher propensity for aggregation.





Keywords: Cluster analysis; Linear regression; Neural network; PCP-descriptors; Protein aggregation; SCOP

Document Type: Research Article

DOI: https://doi.org/10.2174/092986609788923220

Publication date: 2009-08-01

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  • Protein & Peptide Letters publishes short papers in all important aspects of protein and peptide research, including structural studies, recombinant expression, function, synthesis, enzymology, immunology, molecular modeling, drug design etc. Manuscripts must have a significant element of novelty, timeliness and urgency that merit rapid publication. Reports of crystallisation, and preliminary structure determinations of biologically important proteins are acceptable. Purely theoretical papers are also acceptable provided they provide new insight into the principles of protein/peptide structure and function.
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