Carbopeptoid folding: effects of stereochemistry, chain length, and solvent (original) (raw)
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Biopolymers, 2006
The chemical synthesis and single-crystal X-ray diffraction analysis of a model peptide, Boc–Thr–Thr–NH2 (1) comprised of proteinogenic residues bearing an amphiphilic Cβ-stereogenic center, has been described. Interestingly, the analysis of its molecular structure revealed the existence of a distinct conformation that mimics a typical β-turn and Asx-turns, i.e., the two Thr residues occupy the left- and right-corner positions. The main-chain torsion angles of the N- and C-terminal residues i.e., semiextended: ϕ = −68.9°, ψ = 128.6°; semifolded: ϕ = −138.1°, ψ = 2.5° conformations, respectively, in conjunction with a gauche− disposition of the obligatory C-terminus Thr CγH3 group, characterize the occurrence of the newly described β-turn- and Asx-turns-like topology. The preferred molecular structure is suggested to be stabilized by an effective nonconventional main-chain to side-chain CiO · · · HC-type intraturn hydrogen bond. Noteworthy, the observed topology of the resulting 10-membered hydrogen-bonded ring is essentially similar to the one perceived for a classical β-turn and the Asx-turns, stabilized by a conventional intraturn hydrogen bond. Considering the signs as well as magnitudes of the backbone torsion angles and the orientation of the central peptide bond, the overall mimicked topology resembles the type II β-turn or type II Asx-turns. An analysis of Xaa–Thr sequences in high-resolution X-ray elucidated protein structures revealed the novel topology prevalence in functional proteins (unpublished). In view of indubitable structural as well as functional importance of nonconventional interactions in bioorganic and biomacromolecules, we intend to highlight the participation of Thr CγH in the creation of a short-range CO · · · HCγ-type interaction in peptides and proteins. © 2006 Wiley Periodicals, Inc. Biopolymers 81: 440–449, 2006This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
""Three standard gas-phase B3LYP/6-31G(d) methods of the analysis of dC, dH, and JHH NMR data for solutions initially used for the title g-lactams 1aec led to conflicting findings on fractional populations hs of their fast interconverting conformers AeC, which were also inconsistent with energy data. In order to find the source(s) of these discrepancies, several additional DFT computations were carried out at the double- and triple-zeta theory level with simultaneous modeling of the solutions in explicit solvents with the COSMO or IEF-PCM technique. The WC04/WP04 functionals and IGLO-II (or IGLO-III) basis set were applied for predicting dC/dH, and JHH data, respectively. The limits of efficiency and accuracy of a few current NMR-oriented computational protocols were determined by their specific use to the main forms of 1aec treated as test cases. Thus, an unreliability of the modified Karplus-type equation for this purpose was shown. In turn, only the use of DFT-D3 corrections for the attractive van der Waals dispersion interactions (London forces) not present in conventional DFT, to Gibbs free energies (DG) estimated for the forms AeC of 1aec in solution, yielded energetics and so populations (hGs) compatible within 15% (only 2%, for 1a) with the best results found by considering the 1H NMR data. These hHs were found by a linear regression of GIAO-predicted dH sets reproducing experiment in the best way (r2>0.9996, for 1a and 1b, r2=0.9970, for 1c with strongly degenerated dHs). As for hJs, they permitted only for evaluations of the ratios (AþB)/C, excepting sufficiently differentiated JHHs (1b in acetone). In contrast, an application of dCs for assessing hCs was unsuccessful. Selected findings were finally compared with the DP4-probability results (hDP4s) and fairly good agreement was found. The greatest divergence in hs exists for the C=S bond-containing object 1b, what suggests a large effect of the intramolecular London forces on its structure and properties. The present results should be useful guidelines for NMR studies on the other multi-conformer systems in rapid equilibrium between more than two energetically feasible forms.""