Chemometric approach toward protein aggregation propensity

BIOT 231

Mark Cornell Manning, manning@legacybiodesign.com1, Cody M Van Pelt, cvanpelt@legacybiodesign.com1, Robert R. Meglen, bmeglen@LatentStructures.com2, and Fred J. Stevens, fstevens@anl.gov3. (1) Legacy BioDesign LLC, 1826 Monarch Circle, Loveland, CO 80538, (2) Latent Structures, LLC, 500 Manhattan Dr. B-8, Boulder, CO 80303, (3) Argonne National Laboratory, 9700 S. Cass Avenue, Building 202, A-141, Argonne, IL 60439
Replacement of one amino acid for another within a protein sequence alters a number of physicochemical properties at one time (e.g., size, hydrophobicity, polarity). Therefore, a multivariate approach to analyzing the effects of mutation on aggregation propensity must be taken. We have used reduced properties of amino acids and used them to analyze protein sequences, in an effort not only to identity the critical residues, but also the specific physicochemical property at that site having the greatest impact on aggregation rate. The application of this approach to antibody light chains will be presented, along with results on A-beta peptide mutants. In addition, the methodology has been used to study the sequence dependence of conformational stability of the variable region of antibody light chains, as increased conformational stability is critical for retarding aggregation.