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Foldamer Stability Coupled to Aggregation Propensity of Elongated Trp‐Cage Miniproteins
Author(s) -
Farkas Viktor,
Csordás Barbara,
Hegyi Orsolya,
Tóth Gábor K.,
Perczel András
Publication year - 2013
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201300071
Subject(s) - chemistry , circular dichroism , foldamer , crystallography , folding (dsp implementation) , stereochemistry , electrical engineering , engineering
Here we present folding‐associated aggregation propensity of three Trp‐cage foldamers: E0 (20 aa), E5 (25 aa) and E10 (30 aa), models of different sizes but comparable molecular properties. Electronic circular dichroism (ECD), vibrational circular dichroism (VCD) and FT‐IR spectroscopic measurements were used to monitor their concentration‐dependent, heat‐induced (5 °C → 65 °C) “α→β” fold transition. The ECD curves of E0 display an ensemble of highly dynamic structures. ECD of both E5 and E10 foldamers show the expected Trp‐cage fold, dominated by their α‐helical properties. No sign of β‐structures was revealed by ECD at any conditions (5 °C < T < 65 °C, 5 < pH < 7, c ≈ 30 μ M ) for any of these miniproteins. However, at higher concentration ( c ≈ 1–30 m M ) both VCD and FT‐IR spectral features of E5 as well as E10 resemble that of a β‐strand (ca. 1615 cm –1 ), accompanied with “free β‐edges”, or native β‐sheets (ca. 1635 cm –1 ). E5 at lower concentrations ( c ≈ 1–3 m M ), and E10 at higher concentration ( c ≈ 30 m M ) display the α→native‐β→β‐sheet folding transitions, monitored by the characteristic C=O vibrational normal mode frequency shift as follows: ca. 1650 cm –1 → ca. 1635 cm –1 → ca. 1615 cm –1 , respectively. The latter folding path is irreversible. The shortest polypeptide E0 has an “unordered” fold, while E10 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 in preventing the polypeptide backbone chain against self‐aggregation. However, E5 is intermediate in size and stability, and thus among these three polypeptides it is the quickest to aggregate. The present molecular triad, E0, E5 and E10, serves as a good example of larger globular proteins for which aggregation and amyloid fiber‐like nanoparticle formations are often associated with Alzheimer's, Creutzfeldt–Jakob, or prion diseases.