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The role of hydrophobic interactions in initiation and propagation of protein folding.

ABSTRACT: Globular proteins fold by minimizing the nonpolar surface that is exposed to water, while simultaneously providing hydrogen-bonding interactions for buried backbone groups, usually in the form of secondary structures such as alpha-helices, beta-sheets, and tight turns. A primary thermodynamic driving force for the formation of globular structure is thus the sequestration of nonpolar groups, but the correlation between the parts of proteins that are observed to fold first (termed folding initiation sites) and the "hydrophobicity" (as customarily defined) of the amino acids in these regions has been quite weak. It has previously been noted that many amino acid side chains contain considerable nonpolar sections, even if they also contain polar or charged groups. For example, a lysine side chain contains four methylenes, which may undergo hydrophobic interactions if the charged epsilon-NH(3)(+) group is salt-bridged or hydrogen-bonded. Folding initiation sites might therefore contain not only accepted "hydrophobic" amino acids, but also larger charged side chains. Recent experiments on the folding of mutant apomyoglobins provides corroboration for models based on the hypothesis that folding initiation sites arise from hydrophobic interactions. A near-perfect correlation was observed between the areas of the molecule that are present in the burst-phase kinetic intermediate and both the free energy of formation of hydrophobic initiation sites and the parameter "average area buried upon folding," which pinpoints large side chains, even those containing charged or polar portions. These results provide a putative mechanism for the control of protein-folding initiation and growth by polar/nonpolar sequence propensity alone.

SUBMITTER: Dyson HJ

PROVIDER: S-EPMC1559752 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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The role of hydrophobic interactions in initiation and propagation of protein folding.

Dyson H Jane HJ Wright Peter E PE Scheraga Harold A HA

Proceedings of the National Academy of Sciences of the United States of America 20060817 35

Globular proteins fold by minimizing the nonpolar surface that is exposed to water, while simultaneously providing hydrogen-bonding interactions for buried backbone groups, usually in the form of secondary structures such as alpha-helices, beta-sheets, and tight turns. A primary thermodynamic driving force for the formation of globular structure is thus the sequestration of nonpolar groups, but the correlation between the parts of proteins that are observed to fold first (termed folding initiati ...[more]

PMID: 16916929

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Project description:We have designed an automated procedure to cut a protein into compact hydrophobic folding units. The hydrophobic units are large enough to contain tertiary non-local interactions, reflecting potential nucleation sites during protein folding. The quality of a hydrophobic folding unit is evaluated by four criteria. The first two correspond to visual characterization of a structural domain, namely, compactness and extent of isolation. We use the definition of Zehfus and Rose (Zehfus MH, Rose GD, 1986, Biochemistry 25:35-340) to calculate the compactness of a cut protein unit. The isolation of a unit is based on the solvent accessible surface area (ASA) originally buried in the interior and exposed to the solvent after cutting. The third quantity is the hydrophobicity, equivalent to the fraction of the buried non-polar ASA with respect to the total non-polar ASA. The last criterion in the evaluation of a folding unit is the number of segments it includes. To conform with the rationale of obtaining hydrophobic units, which may relate to early folding events, the hydrophobic interactions are implicitly and explicitly applied in their generation and assessment. We follow Holm and Sander (Holm L, Sander C, 1994, Proteins 19:256-268) to reduce the multiple cutting-point problem to a one-dimensional search for all reasonable trial cuts. However, as here we focus on the hydrophobic cores, the contact matrix used to obtain the first non-trivial eigenvector contains only hydrophobic contracts, rather than all, hydrophobic and hydrophilic, interactions. This dataset of hydrophobic folding units, derived from structurally dissimilar single chain monomers, is particularly useful for investigations of the mechanism of protein folding. For cases where there are kinetic data, the one or more hydrophobic folding units generated for a protein correlate with the two or with the three-state folding process observed. We carry out extensive amino acid sequence order independent structural comparisons to generate a structurally non-redundant set of hydrophobic folding units for fold recognition and for statistical purposes.

Dataset Information

The role of hydrophobic interactions in initiation and propagation of protein folding.

Publications

The role of hydrophobic interactions in initiation and propagation of protein folding.

Similar Datasets

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