Browsing by Subject "Conformations"

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Open Access
Protein folding rates correlate with heterogeneity of folding mechanism
(American Physical Society, 2004) Öztop, B.; Ejtehadi, M. R.; Plotkin, S. S.
The folding rates of protein were shown to correlate with the degree of heterogeneity in the formation of native contacts. It was shown that both experimental rates and simulated free energy barriers for 2-state proteins depend on the degree of heterogeneity present in the folding process. Heterogeneity due to variance in the distribution of native loop lengths, and variance in the distribution of φ values, were observed to increase folding rates and reduce folding barriers. The observed effect due to φ variance was found to be the most statistically significant, because φ variance captures both heterogeneity arising from native topology and that arising from energetics.
Open Access
Single-site mutation and secondary structure stability: an isodesmic reaction approach. The case of unnatural amino acid mutagenesis Ala→Lac
(American Chemical Society, 2004) Cieplak, A. S.; Sürmeli, N. B.
A method is described to evaluate backbone interactions in proteins via computational unnatural amino acid mutagenesis. Several N-acetyl polyalanyl amides (AcA nNH 2) were optimized in the representative helical (3 10-, 4 13-, and a "hybrid" κ-helix, n = 7, 9, 10, 14) and hairpin (two- and three-stranded antiparallel β-sheets with type I turns βααε, n =6, 9, 10) conformations, and extended conformers of N-acetyl polyalanyl methylamides (n = 2, 3) were used to derive multistranded β-sheet fragments. Subsequently, each residue of every model structure was substituted, one at a time, with L-lactic acid. The resulting mutant structures were again optimized, and group-transfer energies ΔE GT were obtained as heats of the isodesmic reactions: AcA nNHR + AcOMe → AcA xLacA yNHR + AcNHMe (R = H, C H 3). These group-transfer energies correlate with the degree of charge polarization of the substituted peptide linkages as measured by the difference Δe in H and O Mulliken populations in HN-C=O and with the H-bond distances in the "wild-type" structures. A good correlation obtains for the HF/3-21G and B3LYP/6-31G* group-transfer energies. The destabilization effects are interpreted in terms of loss of interstrand and intrastrand H-bonds, decrease in Lewis basicity of the C-O group, and O⋯O repulsion. On the basis of several comparisons of Ala → Lac ΔE GT's with heats of the NH → CH 2 substitutions, the latter contribution is estimated (B3LYP/6-31G*) to range between 1.5 and 2.4 kcal mol -1, a figure close to the recent experimental ΔδG° value of 2.6 kcal mol -1 (McComas, C. C.; Crowley, B. M.; Boger, D. L. J. Am. Chem. Soc. 2003, 125, 9314). The partitioning yields the following maximum values of the electronic association energy of H-bonds in the examined sample of model structures (B3LYP/6-31G* estimates): 3 10-helix D e = -1.7 kcal mol -1, α-helix D e = -3.8 kcal mol -1 β-sheet D e = -6.1 kcal mol -1. The premise of experimental evaluations of the backbone-backbone H-bonding that Ala → Lac substitution in proteins is isosteric (e.g., Koh, J. T.; Cornish, V. W.; Schultz, P. G. Biochemistry 1997, 36, 11314) is often but not always corroborated. Examination of the integrity of H-bonding pattern and ψ i, ψ i distribution identified several mutants with significant distortions of the "wild-type" structure resulting inter alia from the transitions between i, i + 3 and i, i + 4 H-bonding in helices, observed previously in the crystallographic studies of depsipeptides, (Ohyama, T.; Oku, H.; Hiroki, A.; Maekawa, Y.; Yoshida, M.; Katakai, R. Biopolymers 2000, 54, 875; Karle, I. L.; Das, C.; Balaram, P. Biopolymers 2001, 59, 276). Thus, the isodesmic reaction approach provides a simple way to gauge how conformation of the polypeptide chain and dimensions of the H-bonding network affect the strength of backbone-backbone C=O⋯HN bonds. The results indicate that the stabilization provided by such interactions increases on going from 3 10-helix to α-helix to β-sheet.