β-hairpin-forming peptides; models of early stages of protein folding

Abstract

Formation of β-hairpins is considered the initial step of folding of many proteins and, consequently, peptides constituting the β-hairpin sequence of proteins (the β-hairpin-forming peptides) are considered as models of early stages of protein folding. In this article, we discuss the results of experimental studies (circular-dichroism, infrared and nuclear magnetic resonance spectroscopy, and differential scanning calorimetry) of the structure of β-hairpin-forming peptides excised from the B1 domain of protein G, which are known to fold on their own. We demonstrate that local interactions at the turn sequence and hydrophobic interactions between nonpolar residues are the dominant structure-determining factors, while there is no convincing evidence that stable backbone hydrogen bonds are formed in these peptides in aqueous solution. Consequently, the most plausible mechanism for folding of the β-hairpin sequence appears to be the broken-zipper mechanism consisting of the following three steps: (i) bending the chain at the turn sequence owing to favorable local interactions, (ii) formation of loose hydrophobic contacts between nonpolar residues, which occur close to the contacts in the native structure of the protein but not exactly in the same position and, finally, (iii) formation of backbone hydrogen bonds and locking the hydrophobic contacts in the native positions as a hydrophobic core develops, sufficient to dehydrate the backbone peptide groups. This mechanism provides sufficient uniqueness (contacts form between residues that become close together because the chain is bent at the turn position) and robustness (contacts need not occur at once in the native positions) for folding a β-hairpin sequence.

Molecular dynamics simulation exploration of unfolding and refolding of a ten-amino acid miniprotein

“…The reason why it refolds rapidly is that in initial structure, the turn has not been disrupted thoroughly. As is shown by previous experimental results, b-hairpin formation is initially driven by the bending propensity of the turn segment (Ji and Zhang 2008;Lewandowska et al 2010;Munoz et al 1997). Figure 8b is the radius of gyration of the hydrophobic core.…”

Thermodynamics of protein folding using a modified Wako-Saitô-Muñoz-Eaton model

“…It is well-known that β-hairpins form a considerable number of backbone H-bonds. Additional interactions, such as hydrophobic and electrostatic salt-bridge interactions, among others, are implicitly attributed to the second term in (8). In other words, s i in the M-WSME model is not only a conformational entropy, as in the WSME model, but also a phenomenological parameter that implicitly accounts for all other interactions beyond H-bonding during folding.…”

“…Fitting a β-hairpin peptide to calorimetric data To provide a direct connection between the experiments and models discussed, calorimetric data from the GB1 C-terminal hairpin (41-56) were used to perform the least-square fit 8 to the models. Calorimetric data are from a differential scanning calorimetry (DSC) [55] experiment, which provides an important physical quantity: heat capacity as a function of temperature.…”

“…Anfinsen's thermodynamic hypothesis states that the native state is the most stable conformation among a large number of possible conformations available for a given polypeptide chain [1]. Beginning with Anfinsen's insights, many experimental and theoretical researches have been devoted to protein folding and significant advances have been made over the last few decades [2][3][4][5][6][7][8]. However, because of the size and extreme complexity of the heterogeneous interactions between the surrounding solvent and amino acid residues, the protein folding mechanism is still not fully understood.…”

“…Another example includes a β-hairpin. In their recent review, Scheraga and coworkers discussed a disagreement on the determination of the folding-transition temperature for β-hairpin-forming peptides [8]. They concluded that the disagreement arose because different structure-related features were monitored using different methods.…”