Foldamer stability coupled to aggregation propensity of elongated Trp-cage miniproteins

Farkas, Viktor and Csordás, Barbara and Hegyi, Orsolya and Tóth, Gábor K. and Perczel, András (2013) Foldamer stability coupled to aggregation propensity of elongated Trp-cage miniproteins. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 13. pp. 3513-3522. ISSN 1434-193X

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Here we present folding associated aggregation propensity of three Trp-cage foldamers: E0, E5 and E10, models of different size but still comparable molecular properties. ECD, VCD and FT-IR spectroscopy measurements were used to monitor their concentration dependent, heat induced (5°C 65°C) alpha-beta fold transition. The ECD curves of E0 are referring to an ensemble of highly dynamic structures. ECD of both E5 and E10 foldamers show the expected Trp-cage fold, dominated by their -helical properties. No sign of -structures was revealed by ECD at any conditions (5°C<T<65°C, 5<pH<7, c~30 M) for any of these miniproteins. However, at higher concentration (c~1-30mM) both VCD and FT-IR spectral features of E5 as well as E10 resemble to that of a beta-strand (~1615 cm-1), accompanied with free beta-edges, or native beta-sheets (~1630 cm-1). E5 at lower (c~1-3mM), while E10 at higher concentration (c~30mM) witness the alpha to native-beta to beta-sheet folding transitions, monitored by the characteristic C=O vibrational normal mode frequency shift as follows: ~1650 cm-1, ~1630 cm-1m, ~1615 cm-1, respectively. The latter folding path is irreversible. The shortest polypeptide E0 (20 aa) has an unordered or very dynamic fold, while E10 (30 aa) presents the most tightly packed Trp-cage 3D-structure. We have found that both high dynamicity and/or tight molecular core packing are different in nature, but common in efficacy to prevent the polypeptide backbone chain against self-aggregation. However, E5 is intermediate in size (25 aa) and stability, and thus among these three it is the most vulnerable foldamer against aggregation. The present molecular triad, E0, E5 and E10, serve as a good example of larger globular proteins for which, aggregation and amyloid-fiber like nano-particle formations is often associated with Alzheimer’s, Creutzfeldt–Jakob, or Prion diseases.

Item Type: Article
Subjects: Q Science / természettudomány > QD Chemistry / kémia > QD04 Organic chemistry / szerves kémia
Depositing User: Dóra K. Menyhárd
Date Deposited: 20 Jan 2014 12:56
Last Modified: 27 Feb 2014 13:43

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