Chemometric Study of the Relative Aggregation Propensity of Position 19
Mutants of Aβ(1-42)

Nathaniel   J.   Zbacnik; Mark   Cornell   Manning; Charles   S.   Henry

doi:10.2174/1389203723666220128105334

Abstract

Background: The importance of aromaticity vs. hydrophobicity of the central hydrophobic core (CHC, residues 17-20) in governing fibril formation in Aβ(1-42) has been the focus of an ongoing debate in the literature.

Introduction: Mutations in the CHC (especially at Phe19 and Phe20) have been used to examine the relative impact of hydrophobicity and aromaticity on the degree of aggregation of Aβ(1-42). However, the results have not been conclusive.

Methods: Partial least squares (PLS) modeling of aggregation rates, using reduced properties of a series of position 19 mutants, was employed to identify the physicochemical properties that had the greatest impact on the extent of aggregation.

Results: The PLS models indicate that hydrophobicity at position 19 of Aβ(1-42) appears to be the primary and dominant factor in controlling Aβ(1-42) aggregation, with aromaticity having little effect.

Conclusion: This study illustrates the value of using reduced properties of amino acids in conjunction with PLS modeling to investigate mutational effects in peptides and proteins, as the reduced properties can capture in a quantitative manner the different physicochemical properties of the amino acid side chains. In this particular study, hydrophobicity at position 19 was determined to be the dominant property controlling aggregation, while size, charge, and aromaticity had little impact.

Keywords: Chemometric study, aggregation propensity, Aβ(1-42), mutations, Partial Least Squares (PLS), hydrophobicity.

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DOI https://dx.doi.org/10.2174/1389203723666220128105334	Print ISSN 1389-2037
Publisher Name Bentham Science Publisher	Online ISSN 1875-5550

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Chemometric Study of the Relative Aggregation Propensity of Position 19 Mutants of Aβ(1-42)

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