Water-Mediated Electronic Structure of Oligopeptides Probed by Their UV Circular Dichroism, Absorption Spectra, and Time-Dependent DFT Calculations.

We investigate the UV absorption spectra of a series of cationic GG peptides (where denotes a guest residue) in aqueous solution and find that only a subset of these spectra show a strong dependence with temperature. To explore whether or not this observation reflects conformational dependencies, we carry out time-dependent density functional calculations for the polyproline II (pPII) and β-strand conformations in implicit and explicit water. We find that the calculated CD spectra for pPII can qualitatively account for the experimental spectra irrespective of the water model.

Anticooperative Nearest-Neighbor Interactions between Residues in Unfolded Peptides and Proteins.

Growing evidence suggests that the conformational distributions of amino acid residues in unfolded peptides and proteins depend on the nature of the nearest neighbors. To explore whether the underlying interactions would lead to a breakdown of the isolated pair hypothesis of the classical random coil model, we further analyzed the conformational propensities that were recently obtained for the two guest residues (x,y) of GxyG tetrapeptides. We constructed a statistical thermodynamics model that allows for cooperative as well as for anticooperative interactions between adjacent residues adopting either a polyproline II or a β-strand conformation.

Construction and comparison of the statistical coil states of unfolded and intrinsically disordered proteins from nearest-neighbor corrected conformational propensities of short peptides.

Assessing the influence of nearest neighbors on the conformational ensemble of amino acid residues in unfolded and intrinsically disordered proteins and peptides is pivotal for a thorough understanding of the statistical coil state of unfolded proteins as well as of the energetics of the folding process. Research aimed at exploring nearest neighbor interactions has mostly focused on the analysis of restricted coil libraries that reflect conformational distributions in loops connecting more regular secondary structure segments. Recently, however, Toal et al.

Investigating the Formation of a Repulsive Hydrogel of a Cationic 16mer Peptide at Low Ionic Strength in Water by Vibrational Spectroscopy and Rheology.

The cationic peptide (AAKA) (AK16) exhibits a high propensity for aggregation into β-sheet-like structures in spite of the high positive charge of its protonated lysine side chains. Upon incubation into an aqueous solution, the peptide maintains a metastable β-sheet-like structure with fibrillar content, the apparent stability of which increases with peptide concentration. In the presence of a sufficiently high concentration of anions, the peptide spontaneously forms a hydrogel at millimolar concentrations.

Demixing of water and ethanol causes conformational redistribution and gelation of the cationic GAG tripeptide.

The cationic tripeptide GAG undergoes three conformational changes in binary mixtures of water and ethanol. At 17 mol% of ethanol conformational sampling is shifted from pPII towards β-strands. A more pronounced shift in the same direction occurs at 40 mol%.

Assessing backbone solvation effects in the conformational propensities of amino acid residues in unfolded peptides.

Conformational ensembles of individual amino acid residues within model GxG peptides (x representing different amino acid residues) are dominated by a mixture of polyproline II (pPII) and β-strand like conformations. We recently discovered rather substantial differences between the enthalpic and entropic contributions to this equilibrium for different amino acid residues. Isoleucine and valine exceed all other amino acid residues in terms of their rather large enthalpic stabilization and entropic destabilization of polyproline II.

Randomizing the unfolded state of peptides (and proteins) by nearest neighbor interactions between unlike residues.

To explore the influence of nearest neighbors on conformational biases in unfolded peptides, we combined vibrational and 2D NMR spectroscopy to obtain the conformational distributions of selected "GxyG" host-guest peptides in aqueous solution: GDyG, GSyG, GxLG, GxVG, where x/y=A, K, L, V. Large changes of conformational propensities were observed due to nearest-neighbor interactions, at variance with the isolated pair hypothesis. We found that protonated aspartic acid and serine lose their above-the-average preference for turn-like structures in favor of polyproline II (pPII) populations in the presence of neighbors with bulky side chains.

Entropy reduction in unfolded peptides (and proteins) due to conformational preferences of amino acid residues.

As established by several groups over the last 20 years, amino acid residues in unfolded peptides and proteins do not exhibit the unspecific random distribution as assumed by the classical random coil model. Individual amino acid residues in small peptides were found to exhibit different conformational preferences. Here, we utilize recently obtained conformational distributions of guest amino acid residues in GxG peptides to estimate their conformational entropy, which we find to be significantly lower than the entropy of an assumed random coil like distribution.

Role of enthalpy-entropy compensation interactions in determining the conformational propensities of amino acid residues in unfolded peptides.

The driving forces governing the unique and restricted conformational preferences of amino acid residues in the unfolded state are still not well understood. In this study, we experimentally determine the individual thermodynamic components underlying intrinsic conformational propensities of these residues. Thermodynamic analysis of ultraviolet-circular dichroism (UV-CD) and (1)H NMR data for a series of glycine capped amino acid residues (i.

Disorder and order in unfolded and disordered peptides and proteins: a view derived from tripeptide conformational analysis. II. Tripeptides with short side chains populating asx and β-type like turn conformations.

In the preceding paper, we found that ensembles of tripeptides with long or bulky chains can include up to 20% of various turns. Here, we determine the structural and thermodynamic characteristics of GxG peptides with short polar and/or ionizable central residues (D, N, C), whose conformational distributions exhibit higher than average percentage (>20%) of turn conformations. To probe the side-chain conformations of these peptides, we determined the (3)J(H(α),H(β)) coupling constants and derived the population of three rotamers with χ1 -angles of -60°, 180° and 60°, which were correlated with residue propensities by DFT-calculations.

Ionized trilysine: a model system for understanding the nonrandom structure of poly-L-lysine and lysine-containing motifs in proteins.

It is now well-established that different amino acid residues can exhibit different conformational distributions in the unfolded state of peptides and proteins. These conformational propensities can be modulated by nearest neighbors. In the current study, we combined vibrational and NMR spectroscopy to determine the conformational distributions of the central and C-terminal residues in trilysine peptides in aqueous solution.