Limits...
The energy landscapes of repeat-containing proteins: topology, cooperativity, and the folding funnels of one-dimensional architectures.

Ferreiro DU, Walczak AM, Komives EA, Wolynes PG - PLoS Comput. Biol. (2008)

Bottom Line: The one-dimensional nature of the model implies there are simple relations for the experimental observables: folding free-energy (DeltaG(water)) and the cooperativity of denaturation (m-value), which do not ordinarily apply for globular proteins.To illustrate the ideas, we present a case-study of a family of tetratricopeptide (TPR) repeat proteins and quantitatively relate the results to the experimentally observed folding transitions.Based on the dramatic effect that single point mutations exert on the experimentally observed folding behavior, we speculate that natural repeat proteins are "poised" at particular ratios of inter- and intra-element interaction energetics that allow them to readily undergo structural transitions in physiologically relevant conditions, which may be intrinsically related to their biological functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
Repeat-proteins are made up of near repetitions of 20- to 40-amino acid stretches. These polypeptides usually fold up into non-globular, elongated architectures that are stabilized by the interactions within each repeat and those between adjacent repeats, but that lack contacts between residues distant in sequence. The inherent symmetries both in primary sequence and three-dimensional structure are reflected in a folding landscape that may be analyzed as a quasi-one-dimensional problem. We present a general description of repeat-protein energy landscapes based on a formal Ising-like treatment of the elementary interaction energetics in and between foldons, whose collective ensemble are treated as spin variables. The overall folding properties of a complete "domain" (the stability and cooperativity of the repeating array) can be derived from this microscopic description. The one-dimensional nature of the model implies there are simple relations for the experimental observables: folding free-energy (DeltaG(water)) and the cooperativity of denaturation (m-value), which do not ordinarily apply for globular proteins. We show how the parameters for the "coarse-grained" description in terms of foldon spin variables can be extracted from more detailed folding simulations on perfectly funneled landscapes. To illustrate the ideas, we present a case-study of a family of tetratricopeptide (TPR) repeat proteins and quantitatively relate the results to the experimentally observed folding transitions. Based on the dramatic effect that single point mutations exert on the experimentally observed folding behavior, we speculate that natural repeat proteins are "poised" at particular ratios of inter- and intra-element interaction energetics that allow them to readily undergo structural transitions in physiologically relevant conditions, which may be intrinsically related to their biological functions.

Show MeSH

Related in: MedlinePlus

Molecular dynamic simulations on the folding of TPR proteins using a perfectly funneled topological potential.Representative structures of the native state of TPR proteins with 3, 5, or 7 repeats obtained after simulated annealing. (A) Heat capacity as a function of temperature for CTPR proteins of different number of repeats. The lines correspond to the data for proteins with 3 (solid), 5 (dashed), and 7 (dot-dashed) repeats. Inserts: raw data of the order parameter (Q) as a function of time from representative trajectories close to their respective Tf. (B) Heat capacity as a function of temperature as in b) but for strictly homogeneous set of TPR proteins.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2366061&req=5

pcbi-1000070-g004: Molecular dynamic simulations on the folding of TPR proteins using a perfectly funneled topological potential.Representative structures of the native state of TPR proteins with 3, 5, or 7 repeats obtained after simulated annealing. (A) Heat capacity as a function of temperature for CTPR proteins of different number of repeats. The lines correspond to the data for proteins with 3 (solid), 5 (dashed), and 7 (dot-dashed) repeats. Inserts: raw data of the order parameter (Q) as a function of time from representative trajectories close to their respective Tf. (B) Heat capacity as a function of temperature as in b) but for strictly homogeneous set of TPR proteins.

Mentions: To illustrate the ideas, we simulate the folding of consensus TPR proteins (CTPRs) of different lengths. This is a good test case since high resolution structures are available, making it possible to evaluate the local energetic frustration of the protein [28]. These quantitative measures of frustration show that CTPR is unusually unfrustrated, justifying the use of perfectly funneled models to capture folding. Also, experiments have been already successfully interpreted with a simplified Ising-like description [7], which is also unfrustrated. It is worth noting that even though the sequence of each of the repeats in the consensus protein is the same, there are subtle structural differences that influence the number of contacts made by each repeat, particularly on the end units [33]. The major structural difference is present at the C-terminal repeat which contains an additional ‘capping’ helix. Based on the crystal structure of the 3 repeat protein CTPR3 [33] we constructed a series of proteins for which the terminal repeats are kept constant and the middle one is repeated from 1 to 6 times, thus constructing for computational study a family of proteins that have between 3 and 8 repeats. This family has been realized in the laboratory by Regan et al. [7]. Simulated annealing runs show that the constructed proteins converge to the TPR fold, as expected for this topology-based potential (Figure 4A).


The energy landscapes of repeat-containing proteins: topology, cooperativity, and the folding funnels of one-dimensional architectures.

Ferreiro DU, Walczak AM, Komives EA, Wolynes PG - PLoS Comput. Biol. (2008)

Molecular dynamic simulations on the folding of TPR proteins using a perfectly funneled topological potential.Representative structures of the native state of TPR proteins with 3, 5, or 7 repeats obtained after simulated annealing. (A) Heat capacity as a function of temperature for CTPR proteins of different number of repeats. The lines correspond to the data for proteins with 3 (solid), 5 (dashed), and 7 (dot-dashed) repeats. Inserts: raw data of the order parameter (Q) as a function of time from representative trajectories close to their respective Tf. (B) Heat capacity as a function of temperature as in b) but for strictly homogeneous set of TPR proteins.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2366061&req=5

pcbi-1000070-g004: Molecular dynamic simulations on the folding of TPR proteins using a perfectly funneled topological potential.Representative structures of the native state of TPR proteins with 3, 5, or 7 repeats obtained after simulated annealing. (A) Heat capacity as a function of temperature for CTPR proteins of different number of repeats. The lines correspond to the data for proteins with 3 (solid), 5 (dashed), and 7 (dot-dashed) repeats. Inserts: raw data of the order parameter (Q) as a function of time from representative trajectories close to their respective Tf. (B) Heat capacity as a function of temperature as in b) but for strictly homogeneous set of TPR proteins.
Mentions: To illustrate the ideas, we simulate the folding of consensus TPR proteins (CTPRs) of different lengths. This is a good test case since high resolution structures are available, making it possible to evaluate the local energetic frustration of the protein [28]. These quantitative measures of frustration show that CTPR is unusually unfrustrated, justifying the use of perfectly funneled models to capture folding. Also, experiments have been already successfully interpreted with a simplified Ising-like description [7], which is also unfrustrated. It is worth noting that even though the sequence of each of the repeats in the consensus protein is the same, there are subtle structural differences that influence the number of contacts made by each repeat, particularly on the end units [33]. The major structural difference is present at the C-terminal repeat which contains an additional ‘capping’ helix. Based on the crystal structure of the 3 repeat protein CTPR3 [33] we constructed a series of proteins for which the terminal repeats are kept constant and the middle one is repeated from 1 to 6 times, thus constructing for computational study a family of proteins that have between 3 and 8 repeats. This family has been realized in the laboratory by Regan et al. [7]. Simulated annealing runs show that the constructed proteins converge to the TPR fold, as expected for this topology-based potential (Figure 4A).

Bottom Line: The one-dimensional nature of the model implies there are simple relations for the experimental observables: folding free-energy (DeltaG(water)) and the cooperativity of denaturation (m-value), which do not ordinarily apply for globular proteins.To illustrate the ideas, we present a case-study of a family of tetratricopeptide (TPR) repeat proteins and quantitatively relate the results to the experimentally observed folding transitions.Based on the dramatic effect that single point mutations exert on the experimentally observed folding behavior, we speculate that natural repeat proteins are "poised" at particular ratios of inter- and intra-element interaction energetics that allow them to readily undergo structural transitions in physiologically relevant conditions, which may be intrinsically related to their biological functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
Repeat-proteins are made up of near repetitions of 20- to 40-amino acid stretches. These polypeptides usually fold up into non-globular, elongated architectures that are stabilized by the interactions within each repeat and those between adjacent repeats, but that lack contacts between residues distant in sequence. The inherent symmetries both in primary sequence and three-dimensional structure are reflected in a folding landscape that may be analyzed as a quasi-one-dimensional problem. We present a general description of repeat-protein energy landscapes based on a formal Ising-like treatment of the elementary interaction energetics in and between foldons, whose collective ensemble are treated as spin variables. The overall folding properties of a complete "domain" (the stability and cooperativity of the repeating array) can be derived from this microscopic description. The one-dimensional nature of the model implies there are simple relations for the experimental observables: folding free-energy (DeltaG(water)) and the cooperativity of denaturation (m-value), which do not ordinarily apply for globular proteins. We show how the parameters for the "coarse-grained" description in terms of foldon spin variables can be extracted from more detailed folding simulations on perfectly funneled landscapes. To illustrate the ideas, we present a case-study of a family of tetratricopeptide (TPR) repeat proteins and quantitatively relate the results to the experimentally observed folding transitions. Based on the dramatic effect that single point mutations exert on the experimentally observed folding behavior, we speculate that natural repeat proteins are "poised" at particular ratios of inter- and intra-element interaction energetics that allow them to readily undergo structural transitions in physiologically relevant conditions, which may be intrinsically related to their biological functions.

Show MeSH
Related in: MedlinePlus