Protein Folding Theory: From Lattice to All-Atom Models

Mirny, Leonid A.; Shakhnovich, Eugene I.

doi:10.1146/annurev.biophys.30.1.361

Cited by 333 publications

(270 citation statements)

References 131 publications

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“…The collision-first route enables a high basal folding rate of any protein. Mirny and Shakhnovich (2001) reviewed a number of folding kinetics studies and found that in all cases secondary interactions play-at most-a minor role in determining folding kinetics. Instead, strong and Fig.…”

Section: Direct and Indirect Findings Consistent With The Closed Longmentioning

confidence: 99%

“…The nucleation step was suggested to be a mechanism ensuring a fast and efficient folding transition (Wetlaufer 1973;Fersht 1995Fersht , 1997Mirny and Shakhnovich 2001). The nucleus is formed by residues from different parts of the chain, and unstructured loops between them.…”

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

confidence: 99%

“…The nucleus is formed by residues from different parts of the chain, and unstructured loops between them. In some proteins, the nucleus does not include secondary structures and some proteins do have secondary structures in their folding nucleus, which depend on stabilization by NLIs (Mirny and Shakhnovich 2001). A very large body of theoretical, simulations and experimental studies further developed the role of nucleation as a step of the folding transition (Daggett and Fersht 2003).…”

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

confidence: 99%

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

et al. 2013

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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.

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Section: Direct and Indirect Findings Consistent With The Closed Longmentioning

confidence: 99%

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

confidence: 99%

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

confidence: 99%

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

et al. 2013

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“…The discovery of a class of simple, single-domain proteins which fold via two-state kinetics without any detectable intermediates in the early 1990s [6,7], the development of experimental techniques with improved spatial/temporal resolution [8][9][10][11][12][13], and the application of computer simulations using simplified lattice and off-lattice models [14,15] greatly enhanced our understanding of various aspects of the protein folding problem. Based on the nucleation theory [16][17][18], one of the early proposed mechanisms for protein folding, the nucleation-condensation model was formulated [19][20][21].…”

Section: Studying Protein Foldingmentioning

confidence: 99%

Protein folding: Then and now

Chen

Ding

Nie

et al. 2008

Archives of Biochemistry and Biophysics

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Over the past three decades the protein folding field has undergone monumental changes. Originally a purely academic question, how a protein folds has now become vital in understanding diseases and our abilities to rationally manipulate cellular life by engineering protein folding pathways. We review and contrast past and recent developments in the protein folding field. Specifically, we discuss the progress in our understanding of protein folding thermodynamics and kinetics, the properties of evasive intermediates, and unfolded states. We also discuss how some abnormalities in protein folding lead to protein aggregation and human diseases.

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“…They can be seen as a generic formulation of combinatorial optimization problems in computer science and operations research (Garey and Johnson 1979), they describe the Hamiltonians of disordered systems in physics (Binder and Young 1986;Mézard et al 1987;Ferreira et al 2000), and they are (discretized versions of) potential energy surfaces in theoretical chemistry (Mezey 1987). In structural biology, energy landscapes are used to understand the folding of biopolymers into their three-dimensional structures, and discrete versions are used to study folding processes at the level of lattice protein models (Mirny and Shakhnovich 2001) and RNA secondary structures (Flamm and Hofacker 2008).…”

Section: Introductionmentioning

confidence: 99%

Combinatorial vector fields and the valley structure of fitness landscapes

Stadler

2010

J. Math. Biol.

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Adaptive (downhill) walks are a computationally convenient way of analyzing the geometric structure of fitness landscapes. Their inherently stochastic nature has limited their mathematical analysis, however. Here we develop a framework that interprets adaptive walks as deterministic trajectories in combinatorial vector fields and in return associate these combinatorial vector fields with weights that measure their steepness across the landscape. We show that the combinatorial vector fields and their weights have a product structure that is governed by the neutrality of the landscape. This product structure makes practical computations feasible. The framework presented here also provides an alternative, and mathematically more convenient, way of defining notions of valleys, saddle points, and barriers in landscape. As an application, we propose a refined approximation for transition rates between macrostates that are associated with the valleys of the landscape.

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Protein Folding Theory: From Lattice to All-Atom Models

Cited by 333 publications

References 131 publications

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

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

Protein folding: Then and now

Combinatorial vector fields and the valley structure of fitness landscapes

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