Article

Alternate Pathways for Folding in the Flavodoxin Fold Family Revealed by a Nucleation-growth Model

Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6001 Forest Park Blvd., Room ND10.124, Dallas, TX 75235-9050, USA.
Journal of Molecular Biology (Impact Factor: 4.33). 06/2006; 358(3):646-53. DOI: 10.1016/j.jmb.2006.02.026
Source: PubMed

ABSTRACT

A recent study of experimental results for flavodoxin-like folds suggests that proteins from this family may exhibit a similar, signature pattern of folding intermediates. We study the folding landscapes of three proteins from the flavodoxin family (CheY, apoflavodoxin, and cutinase) using a simple nucleation and growth model that accurately describes both experimental and simulation results for the transition state structure, and the structure of on-pathway and misfolded intermediates for CheY. Although the landscape features of these proteins agree in basic ways with the results of the study, the simulations exhibit a range of folding behaviours consistent with two alternate folding routes corresponding to nucleation and growth from either side of the central beta-strand.

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    • "One of those questions pertains to the influence of the water environment upon the folding process. The presence of the hydrophobic core and its role in ensuring tertiary structural stabilization is well established (Hamill et al., 2000; Nelson and Grishin, 2006; Lazar and Handel, 1998; Yang et al., 2012; Koide et al., 2000; Ryu et al., 1996; Chen and Stites, 1959). The reason we refer to a fairly old work (Kauzmann 1959) is to highlight the commonalities between the model proposed in this publication and our own fuzzy oil drop model. "
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    ABSTRACT: In this paper we show that the fuzzy oil drop model represents a general framework for describing the generation of hydrophobic cores in proteins and thus provides insight into the influence of the water environment upon protein structure and stability. The model has been successfully applied in the study of a wide range of proteins, however this paper focuses specifically on domains representing immunoglobulin-like folds. Here we provide evidence that immunoglobulin-like domains, despite being structurally similar, differ with respect to their participation in the generation of hydrophobic core. It is shown that β-structural fragments in β-barrels participate in hydrophobic core formation in a highly differentiated manner. Quantitatively measured participation in core formation helps explain the variable stability of proteins and is shown to be related to their biological properties. This also includes the known tendency of immunoglobulin domains to form amyloids, as shown using transthyretin to reveal the clear relation between amyloidogenic properties and structural characteristics based on the fuzzy oil drop model.
    Preview · Article · May 2014 · Journal of Theoretical Biology
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    • "One of those questions pertains to the influence of the water environment upon the folding process. The presence of the hydrophobic core and its role in ensuring tertiary structural stabilization is well established (Hamill et al., 2000; Nelson and Grishin, 2006; Lazar and Handel, 1998; Yang et al., 2012; Koide et al., 2000; Ryu et al., 1996; Chen and Stites, 1959). The reason we refer to a fairly old work (Kauzmann 1959) is to highlight the commonalities between the model proposed in this publication and our own fuzzy oil drop model. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this paper we show that the fuzzy oil drop model represents a general framework for describing the generation of hydrophobic cores in proteins and thus provides insight into the influence of the water environment upon protein structure and stability. The model has been successfully applied in the study of a wide range of proteins, however this paper focuses specifically on domains representing immunoglobulin-like folds. Here we provide evidence that immunoglobulin-like domains, despite being structurally similar, differ with respect to their participation in the generation of hydrophobic core. It is shown that β-structural fragments in β-barrels participate in hydrophobic core formation in a highly differentiated manner. Quantitatively measured participation in core formation helps explain the variable stability of proteins and is shown to be related to their biological properties. This also includes the known tendency of immunoglobulin domains to form amyloids, as shown using transthyretin to reveal the clear relation between amyloidogenic properties and structural characteristics based on the fuzzy oil drop model.
    Preview · Article · Jan 2014 · Journal of Theoretical Biology
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    • "In these potentials, amino acids that are in contact in the native structure attract each other, while amino acids not in contact in the native structure repel each other, irrespective, at least to some extent, of the physical interactions between the amino acids. The second class of models assumes that amino acids can be in either of two states: native-like structured, or unstructured [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78]. Partially folded states then are described by sets of structured amino acids. "
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    ABSTRACT: Simple theoretical concepts and models have been helpful to understand the folding rates and routes of single-domain proteins. As reviewed in this article, a physical principle that appears to underly these models is loop closure. Key words: protein folding kinetics, native-state topology, two-state proteins, folding rates, contact order, topological measures, folding routes, loop-closure entropy, effective contact order 1 Topology and loop closure The topic of this review is the relation between the folding kinetics of proteins and their three-dimensional, native structures. Central questions concerning the folding kinetics are: How do proteins fold into their native structures, and what are the rates and routes of folding? Since their discovery in 1991 [1], two-state proteins have been in the focus of experimental studies [2–5]. These proteins fold from the denatured state to the native state without experimentally detectable intermediate states. The size of most two-state proteins is rather similar, roughly between 60 and 120 residues, with a few smaller
    Preview · Article · Feb 2008 · Archives of Biochemistry and Biophysics
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