Specific Nucleus as the Transition State for Protein Folding: Evidence from the Lattice Model

Abkevich, Victor; Gutin, A. M.; Shakhnovich, Eugene I.

doi:10.1021/bi00199a029

Cited by 476 publications

(492 citation statements)

References 66 publications

Supporting

Mentioning

451

Contrasting

Unclassified

Order By: Relevance

“…The original MJ potential (Table V of [329]), as was used in [40,153,296,330], embodies the hydrophobic effect, thus it tends to place non-polar residues in the folded protein core as in real proteins (reviewed in [116,204]). However, certain modified, 'shifted' forms of MJ potentials that are similar to table VI of [329] with prominent repulsive energies [331] do not embody this biophysical property (reviewed in [158,204]), making it problematic to interpret some of the predictions from such models. For instance, in some cases, a shifted-MJ potential may lead to nominally charged residues instead of hydrophobic residues occupying the core of a model protein [114,204,331].…”

Section: Model Interactions and Their Biophysical Basismentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

224

207

View full text Add to dashboard Cite

The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence-structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by 'hidden' conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution.

show abstract

Section: Model Interactions and Their Biophysical Basismentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

224

207

View full text Add to dashboard Cite

show abstract

“…Using lattice simulations as mentioned above, Abkevich et al (1994) observed that a structure with mostly non-local contacts folded two orders of magnitude faster than one with mostly local contacts. Juraszky et al (Juraszek and Bolhuis 2006) found that in the folding of the small protein, i.e., the WW cage, 80 % of the pathways are initiated by NLI while secondary structures appear later.…”

Section: O'neill Et Al (O'neill and Robert Matthews 2000)mentioning

confidence: 97%

The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

et al. 2013

View full text Add to dashboard Cite

The extremely fast and efficient folding transition (in seconds) of globular proteins led to the search for some unifying principles embedded in the physics of the folding polypeptides. Most of the proposed mechanisms highlight the role of local interactions that stabilize secondary structure elements or a folding nucleus as the starting point of the folding pathways, i.e., a "bottom-up" mechanism. Nonlocal interactions were assumed either to stabilize the nucleus or lead to the later steps of coalescence of the secondary structure elements. An alternative mechanism was proposed, an "up-down" mechanism in which it was assumed that folding starts with the formation of very few non-local interactions which form closed long loops at the initiation of folding. The possible biological advantage of this mechanism, the "loop hypothesis", is that the hydrophobic collapse is associated with ordered compactization which reduces the chance for degradation and misfolding. In the present review the experiments, simulations and theoretical consideration that either directly or indirectly support this mechanism are summarized. It is argued that experiments monitoring the time-dependent development of the formation of specifically targeted early-formed sub-domain structural elements, either long loops or secondary structure elements, are necessary. This can be achieved by the timeresolved FRET-based "double kinetics" method in combination with mutational studies. Yet, attempts to improve the time resolution of the folding initiation should be extended down to the sub-microsecond time regime in order to design experiments that would resolve the classes of proteins which first fold by local or non-local interactions.

show abstract

“…Several other small single domain proteins were later shown to fold in a similar way [3]. The two state mechanism provided the basis for a nucleation-condensation mechanism, with folding through simultaneous formation of secondary and tertiary structure centered around a small folding nucleus [4,5]. Recent work on the homeodomain superfamily [6,7] and on a PDZ domain [8], led to the view that the framework and nucleation-condensation models represent extreme manifestation of an underlying common mechanism and that proteins may appear to fold by either the nucleation-condensation or framework mechanism depending on the inherent stability of their secondary structure elements [7,9].…”

Section: Introductionmentioning

confidence: 98%

Identification and characterization of protein folding intermediates

Gianni

Ivarsson

Jemth

et al. 2007

Biophysical Chemistry

View full text Add to dashboard Cite

In order to understand the mechanism by which a polypeptide chain folds into its functionally active native state it is necessary to characterize in detail all the species accumulated along the pathway.The elusive nature of protein folding intermediates poses their identification and characterization as an extremely difficult task in the protein folding field. In the case of small single domain proteins, the direct measurement of the thermodynamics and structural parameters of protein folding intermediates has provided new insights on the nature of the forces involved in the stabilization of nascent protein structures. Here we summarize some of the experimental approaches aimed at the detection and characterization of folding intermediates along with a discussion of some general structural features emerging from these studies.

show abstract

Specific Nucleus as the Transition State for Protein Folding: Evidence from the Lattice Model

Cited by 476 publications

References 66 publications

Biophysics of protein evolution and evolutionary protein biophysics

Biophysics of protein evolution and evolutionary protein biophysics

The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

Identification and characterization of protein folding intermediates

Contact Info

Product

Resources

About