A Method for Predicting Nucleation Sites for Protein Folding Based on Hydrophobic Contacts

Matheson, R. R.; Scheraga, Harold A.

doi:10.1021/ma60064a038

Cited by 212 publications

(174 citation statements)

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“…Starting from the proposed folding region (residues 106-118, [22]) and unfolding region (residues 31-46, [25]) of RNase A, we introduced extra disulfide bonds and studied the effect on the thermodynamic stability and folding/unfolding reaction of the variants in comparison to RNase A. Regardless of the position of the extra disulfide bond, the main effect for both stabilized and destabilized variants was exerted via k U (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…The folding region of RNase A had been postulated for residues 106-118 ( Fig. 1; [22]) and its importance for the folding and stability of the RNase A molecule has been confirmed by mutagenesis studies [23] or replacement of cisPro114 by the cis-locked β-turn mimic 5',5'-dimethylproline [24]. As for the unfolding process, the section from the C-terminal end of helix II (Lys31) through the first β-sheet strand (Phe46) became susceptible first to proteolytic attack by thermolysin and trypsin under denaturing conditions [25] and several residues in this region showed a faster H-D exchange than that of global unfolding [26,27].…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

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The effect of additional disulfide bonds on the stability and folding of ribonuclease A

Pecher¹,

Arnold²

2009

Biophysical Chemistry

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International audienceThe significant contribution of disulfide bonds to the conformational stability of proteins is generally considered to result from an entropic destabilization of the unfolded state causing a faster escape of the molecules to the native state. However, the introduction of extra disulfide bonds into proteins as a general approach to protein stabilization yields rather inconsistent results. By modeling studies, we selected positions to introduce additional disulfide bonds into ribonuclease A at regions that had proven to be crucial for the initiation of the folding or unfolding process, respectively. However, only two out of the six variants proved to be more stable than unmodified ribonuclease A. The comparison of the thermodynamic and kinetic data disclosed a more pronounced effect on the unfolding reaction for all variants regardless of the position of the extra disulfide bond. Native-state proteolysis indicated a perturbation of the native state of the destabilized variants that obviously counterbalances the stability gain by the extra disulfide bond

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Section: Discussionmentioning

confidence: 99%

Section: Accepted M Manuscriptmentioning

confidence: 99%

The effect of additional disulfide bonds on the stability and folding of ribonuclease A

Pecher¹,

Arnold²

2009

Biophysical Chemistry

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“…8 Understanding the intramolecular interactions that govern the formation of these intermediates would represent an important advance towards solving the protein-folding problem. [9][10][11][12] Reductive unfolding, the converse of oxidative folding, is the process by which a disulfidebond-containing protein loses its native structure (unfolds) through the (successive) reduction of its disulfide bonds. [13][14][15][16][17][18][19][20][21] In reductive unfolding, protein disulfide bonds scattered throughout the macromolecular architecture can serve as reporter groups for probing local fluctuations within the folded polypeptide; these fluctuations eventually lead to the unfolding of the whole molecule.…”

Section: Introductionmentioning

confidence: 99%

A Localized Specific Interaction Alters the Unfolding Pathways of Structural Homologues

Narayan

Kurinov

et al. 2006

J. Am. Chem. Soc.

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Reductive unfolding studies of proteins are designed to provide information about intramolecular interactions that govern the formation (and stabilization) of the native state and about folding/ unfolding pathways. By mutating Tyr92 to G, A, or L in the model protein, bovine pancreatic ribonuclease A, and through analysis of temperature factors and molecular dynamics simulations of the crystal structures of these mutants, it is demonstrated that the markedly different reductive unfolding rates and pathways of ribonuclease A and its structural homologue onconase can be attributed to a single, localized, ring-stacking interaction between Tyr92 and Pro93 in the bovine variant. The fortuitous location of this specific stabilizing interaction in a disulfide-bond-containing loop region of ribonuclease A results in the localized modulation of protein dynamics which, in turn, enhances the susceptibility of the disulfide bond to reduction leading to an alteration in the reductive unfolding behavior of the homologues. These results have important implications for folding studies involving topological determinants to obtain folding/unfolding rates and pathways, for protein structure-function prediction through fold recognition, and for predicting proteolytic cleavage sites.

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“…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 -NH 3 ؉ group is saltbridged or hydrogen-bonded. Folding initiation sites might therefore contain not only accepted ''hydrophobic'' amino acids, but also larger charged side chains.…”

mentioning

confidence: 99%

“…Because nonpolar groups are not soluble in water, attention has been focused on the hydrophobic interactions between nonpolar side chains to achieve their sequestration from aqueous solvent. A model has been proposed in which nearby nonpolar groups in the chain participate in hydrophobic interactions with minimal loss of entropy of the chain because of the proximity of the interacting side chains in the amino acid sequence (3).…”

mentioning

confidence: 99%

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

Dyson

Wright

Scheraga

2006

Proc. Natl. Acad. Sci. U.S.A.

284

217

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Globular proteins fold by minimizing the nonpolar surface that is exposed to water, while simultaneously providing hydrogenbonding interactions for buried backbone groups, usually in the form of secondary structures such as ␣-helices, ␤-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 -NH 3 ؉ group is saltbridged 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 burstphase 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 polar͞nonpolar sequence propensity alone.folding pathways ͉ myoglobin ͉ ribonuclease F reed of the ribosome, and in the absence of chaperones, a newly synthesized protein exists in an ensemble of states, the so-called statistical coil, the nature of which is a subject of much recent investigation (1). It subsequently folds to the native biologically active structure whose free energy is considered to be a minimum under appropriate solution conditions (2). Since the seminal work of Anfinsen (2), the kinetics of the folding process and the final structure have been considered to be determined by the physical interactions among the amino acid residues to attain the thermodynamically favored state.A major question has involved the exact mechanism by which the interresidue interactions specify the initiation of folding in the unfolded polypeptide chain under folding conditions. Because nonpolar groups are not soluble in water, attention has been focused on the hydrophobic interactions between nonpolar side chains to achieve their sequestration from aqueous solvent. A model has been proposed in which nearby nonpolar groups in the chain participate in hydrophobic interactions with minimal loss of entropy of the chain because of the proximity of the interacting side chains in the amino acid sequence (3).Yet the chemical nature of the polypeptide chain complicates ...

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A Method for Predicting Nucleation Sites for Protein Folding Based on Hydrophobic Contacts

Cited by 212 publications

References 17 publications

The effect of additional disulfide bonds on the stability and folding of ribonuclease A

The effect of additional disulfide bonds on the stability and folding of ribonuclease A

A Localized Specific Interaction Alters the Unfolding Pathways of Structural Homologues

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

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