Antibody recognition and conformational flexibility of a plaque-specific beta-amyloid epitope modulated by non-native peptide flanking regions.
Here we report on the synthesis, antibody binding, and QSAR studies of a series of linear and cyclic peptides containing a beta-amyloid plaque-specific epitope (Abeta(4-10); FRHDSGY). In these constructs, two or three alpha- l-Ala, alpha- d-Ala, or beta-Ala residues were introduced at both N- and C-termini of the epitope as non-native flanking sequences. Cyclization of the linear Abeta(4-10) epitope peptide resulted in reduced antibody binding. However, the antibody binding could be fully compensated by insertion of alanine flanks into the corresponding cyclic peptides. These results indicate that the modification of a beta-amyloid plaque-specific epitope by combination of cyclization and flanking sequences could generate highly antigenic peptides compared to the native sequence. A novel 3D QSAR method, which explicitly handles conformational flexibility, was developed for the case of such molecular libraries. This method led to the prediction of the binding conformation for the common FRHDSGY sequence.
Manea
Marilena
M
Laboratory of Analytical Chemistry and Biopolymer Structure Analysis, University of Konstanz, 78457 Konstanz, Germany.
Kalászi
Adrián
A
Mezo
Gábor
G
Horváti
Kata
K
Bodor
Andrea
A
Horváth
Anikó
A
Farkas
Odön
O
Perczel
András
A
Przybylski
Michael
M
Hudecz
Ferenc
F
D000409:Alanine / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry*; D058225:Plaque, Amyloid / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D012996:Solutions
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D000939:Epitopes; D010456:Peptides, Cyclic; D012996:Solutions; D000409:Alanine