The role of hydrophobic interactions in folding of $\beta$-sheets

TL;DR

This paper investigates how hydrophobic interactions among side-chains drive the folding of β-sheets, revealing that hydrophobic surface areas are crucial in the folding process and can be deciphered from amino acid sequences.

Contribution

It demonstrates that hydrophobic interactions are fundamental in β-sheet folding and provides bioinformatics evidence supporting a multistage hydrophobic mechanism for protein folding.

Findings

Hydrophobic surface area is prevalent in most β-sheets.

Folding is driven by multistage hydrophobic interactions among side-chains.

Hydrophobic effect strength explains temperature dependence of folding.

Abstract

Exploring the protein-folding problem has been a long-standing challenge in molecular biology. Protein folding is highly dependent on folding of secondary structures as the way to pave a native folding pathway. Here, we demonstrate that a feature of a large hydrophobic surface area covering most side-chains on one side or the other side of adjacent $\beta$-strands of a $\beta$-sheet is prevail in almost all experimentally determined $\beta$-sheets, indicating that folding of $\beta$-sheets is most likely triggered by multistage hydrophobic interactions among neighbored side-chains of unfolded polypeptides, enable $\beta$-sheets fold reproducibly following explicit physical folding codes in aqueous environments. $\beta$-turns often contain five types of residues characterized with relatively small exposed hydrophobic proportions of their side-chains, that is explained as these residues can block hydrophobic effect among neighbored side-chains in sequence. Temperature dependence of the folding of $\beta$-sheet is thus attributed to temperature dependence of the strength of the hydrophobicity. The hydrophobic-effect-based mechanism responsible for $\beta$-sheets folding is verified by bioinformatics analyses of thousands of results available from experiments. The folding codes in amino acid sequence that dictate formation of a $\beta$-hairpin can be deciphered through evaluating hydrophobic interaction among side-chains of an unfolded polypeptide from a $\beta$-strand-like thermodynamic metastable state.