Formation of local structures in protein folding

Montelione, Gaetano T.; Scheraga, Harold A.

doi:10.1021/ar00158a004

Cited by 105 publications

(90 citation statements)

References 105 publications

(22 reference statements)

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“…The first approach (3) identified the primary initiation sites in 14 proteins, including bovine pancreatic RNase A and sperm whale myoglobin, and also other less-stable initiation sites (11) in RNase A. The primary initiation site for RNase A was identified in this model as residues 106-118.…”

Section: Experimental Verification Of Modelsmentioning

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.

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280

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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Section: Experimental Verification Of Modelsmentioning

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.

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280

217

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“…This view gained credence from the partial success of (1) models, both computational and experimental, of peptides and protein pieces, and (2) database methods that rationalize helical, sheet, and turn propensities in proteins (Chou et al, 1972;Anfinsen & Scheraga, 1975;Montelione & Scheraga, 1989). Hydrophobicity was seen as "nonspecific," and hydrogen bonding and helical propensities were seen as the "specific" components of the folding code that directs a protein to fold to its unique native structure.…”

Section: Nonlocal Forces: Hydrophobic Interactions Are Importantmentioning

confidence: 99%

Principles of protein folding — A perspective from simple exact models

et al. 1995

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General principles of protein structure, stability, and folding kinetics have recently been explored in computer simulations of simple exact lattice models. These models represent protein chains at a rudimentary level, but they involve few parameters, approximations, or implicit biases, and they allow complete explorations of conformational and sequence spaces. Such simulations have resulted in testable predictions that are sometimes unanticipated: The folding code is mainly binary and delocalized throughout the amino acid sequence. The secondary and tertiary structures of a protein are specified mainly by the sequence of polar and nonpolar monomers. More specific interactions may refine the structure, rather than dominate the folding code. Simple exact models can account for the properties that characterize protein folding: two-state cooperativity, secondary and tertiary structures, and multistage folding kinetics-fast hydrophobic collapse followed by slower annealing. These studies suggest the possibility of creating "foldable" chain molecules other than proteins. The encoding of a unique compact chain conformation may not require amino acids; it may require only the ability to synthesize specific monomer sequences in which at least one monomer type is solvent-averse.Keywords: chain collapse; hydrophobic interactions; lattice models; protein conformations; protein folding; protein stabilityWe review the principles of protein structure, stability, and folding kinetics from the perspective of simple exact models. We focus on the "folding code''-how the tertiary structure and folding pathway of a protein are encoded in its amino acid sequence. Although native proteins are specific, compact, and often remarkably symmetrical structures, ordinary synthetic polymers in solution, glasses, or melts adopt large ensembles of more expanded conformations, with little intrachain organization. With simple exact models, we ask what are the fundamental causes of the differences between proteins and other polymers-What makes proteins special?One view of protein folding assumes that the "local" interactions among the near neighbors in the amino acid sequence, the interactions that form helices and turns, are the main determinants of protein structure. This assumption implies that isolated helices form early in the protein folding pathway and then assemble into the native tertiary structure (see Fig. 1). It is the premise behind the paradigm, primary + secondary -+ tertiary structure, that seeks computer algorithms to predict secondary structures from the sequence, and then to assemble them into the tertiary native structure.Here we review a simple model of an alternative view, its basis in experimental results, and its implications. We show how the nonlocal interactions that drive collapse processes in heteropolymers can give rise to protein structure, stability, and folding kinetics. This perspective is based on evidence that the folding code is not predominantly localized in short windows of the amino acid sequence. It...

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“…To investigate the nature of the conformational ensembles in the unfolded protein and the early folding events in RNase A, we combined ultrafast continuous-flow (CF) and conventional stopped-flow (SF) mixing techniques to monitor folding of a single-tryptophan variant of RNase A, Y92W, which contains a sensitive fluorescence probe in a region of the protein implicated in early folding events (10). This mutant has been reported to exhibit a major burst phase in double-jump stopped-flow fluorescence experiments (11).…”

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confidence: 99%

Ultrarapid mixing experiments shed new light on the characteristics of the initial conformational ensemble during the folding of ribonuclease A

Welker

Maki

Shastry

et al. 2004

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

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The earliest folding events in single-tryptophan mutants of RNase A were investigated by fluorescence measurements by using a combination of stopped-flow and continuous-flow mixing experiments covering the time range from 70 s to 10 s. An ultrarapid double-jump mixing protocol was used to study refolding from an unfolded ensemble containing only native proline isomers. The continuous-flow measurements revealed a series of kinetic events on the submillisecond time scale that account for the burst-phase signal observed in previous stopped-flow experiments. An initial increase in fluorescence within the 70-s dead time of the continuous-flow experiment is consistent with a relatively nonspecific collapse of the polypeptide chain whereas a subsequent decrease in fluorescence with a time constant of Ϸ80 s is indicative of a more specific structural event. These rapid conformational changes are not observed if RNase A is allowed to equilibrate under denaturing conditions, resulting in formation of nonnative proline isomers. Thus, contrary to previous expectations, the isomerization state of proline peptide bonds can have a major impact on the structural events during early stages of folding.burst phase ͉ continuous-flow ͉ proline isomers ͉ stopped-flow

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Formation of local structures in protein folding

Cited by 105 publications

References 105 publications

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

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

Principles of protein folding — A perspective from simple exact models

Ultrarapid mixing experiments shed new light on the characteristics of the initial conformational ensemble during the folding of ribonuclease A

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