Document Detail

Triaspartate: A Model System for Conformationally Flexible DDD Motifs in Proteins.
MedLine Citation:
PMID:  22435395     Owner:  NLM     Status:  Publisher    
Understanding the interactions which govern turn formation in the unfolded state of proteins is necessary for a complete picture of the role these turns play in both normal protein folding and functionally relevant yet disordered linear motifs. It is still unclear, however, whether short peptides can adopt stable turn structures in aqueous environments in the absence of any non-local interactions. To explore the effect nearest neighbor interactions and local peptide environment have on turn-forming capability of individual amino acid residues in short peptides, we combined vibrational (IR, Raman, and VCD), UVCD, and 1H NMR spectroscopies in order to probe the conformational ensemble of the central aspartic acid residue of the triaspartate peptide (DDD). The study was motivated by the recently discovered turn propensities of aspartic acid in GDG (Hagarman et al., Chem. Eur. J. 17, 6789, 2011). We investigated the DDD peptide under both acidic and neutral conditions in order to elucidate the effect side-chain protonation has on the conformational propensity of the central aspartic acid residue. Amide I' profiles were analyzed in terms of two-dimensional Gaussian distributions representing conformational sub-distributions in Ramachandran space. Interestingly, our results show that while the protonated form of the DDD peptide samples various turn-like conformations similar to GDG, deprotonation of the peptide eliminates this propensity for turns causing the fully ionized peptide to exclusively sample pPII and β-strand like structures. To further explore the factors stabilizing these more extended conformations in fully ionized DDD, we analyzed the temperature dependence of both the UVCD-spectrum and the 3J(HN, Hα)-coupling constants of the two amide protons (N- and C-terminal) in terms of a simple two state (pPII-β) thermodynamic model. For the N-terminal we obtain ∆H2= -11.2kJ/mol and ∆S2= -34.6J/mol∙K, yielding a small Gibbs free energy difference of 0.96kJ/mol at room temperature. For the C-terminal, we obtain ΔH3.= -12.0kJ/mol ΔS3.= -73.8J/mol*K, resulting in a much larger room temperature Gibbs free energy of 10.0kJ/mol, which effectively locks the C-terminal in a β-like conformation. A comparison of the temperature dependence of the chemical shifts reveals that there is indeed some type of protection of the amide protons from solvent in ionized DDD. This finding and several other lines of evidence suggest that both conformations of ionized DDD are stabilized by hydrogen bonding between the carboxylate groups of the central and C-terminal residue and the respective amide protons. These hydrogen bonds can be expected to be eliminated by side chain protonation and substituted by hydrogen bonds between the N-terminal amide proton and the C-terminal carbonyl group as well as between the central aspartate side chain and the N-terminal amide proton. Hence, our results are indicative of a pH-induced switch in hydrogen bonding patterns of aspartic acid motifs.
Laura Duitch; Siobhan Toal; Thomas J Measey; Reinhard Schweitzer-Stenner
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-21
Journal Detail:
Title:  The journal of physical chemistry. B     Volume:  -     ISSN:  1520-5207     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101157530     Medline TA:  J Phys Chem B     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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