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Knotted proteins: A tangled tale of Structural Biology.

Faísca PF - Comput Struct Biotechnol J (2015)

Bottom Line: Knotted proteins have their native structures arranged in the form of an open knot.Molecular simulations have been playing a fundamental role in this endeavor, and early computational predictions about the knotting mechanism have just been confirmed in wet lab experiments.Here we review a collection of simulation results that allow outlining the current status of the field of knotted proteins, and discuss directions for future research.

View Article: PubMed Central - PubMed

Affiliation: Departament of Physics and BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa, Portugal.

ABSTRACT
Knotted proteins have their native structures arranged in the form of an open knot. In the last ten years researchers have been making significant efforts to reveal their folding mechanism and understand which functional advantage(s) knots convey to their carriers. Molecular simulations have been playing a fundamental role in this endeavor, and early computational predictions about the knotting mechanism have just been confirmed in wet lab experiments. Here we review a collection of simulation results that allow outlining the current status of the field of knotted proteins, and discuss directions for future research.

No MeSH data available.


Related in: MedlinePlus

Knotting probability pknot, as a function of the folding probability, pfold (a) and as a function of fraction of formed native contacts, Q (b) in three lattice Go proteins: a shallow trefoil knot, a deep trefoil obtained from the first by extending the knot tails, and a shallow 52 knot. In the three dimensional structures the knotted core is highlighted. The three model systems fold with a thermodynamic two-state transition (data not shown) and the transition state ensemble comprises conformations in the region highlighted in pink. For both shallow and deep trefoils pknot shows a sigmoidal dependence on Q and there is a non-negligible probability for knotting and folding to occur concomitantly. For the more complex knot type knotting occurs in highly native-like conformations (Q > 0.8). pknot is the fraction of knotted conformations in very large ensembles of conformations (with fraction of native contacts Q or folding probability pfold) that are extracted from an equilibrium distribution at the temperature of interest. Details on the calculation of pfold can be found in [25].
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f0020: Knotting probability pknot, as a function of the folding probability, pfold (a) and as a function of fraction of formed native contacts, Q (b) in three lattice Go proteins: a shallow trefoil knot, a deep trefoil obtained from the first by extending the knot tails, and a shallow 52 knot. In the three dimensional structures the knotted core is highlighted. The three model systems fold with a thermodynamic two-state transition (data not shown) and the transition state ensemble comprises conformations in the region highlighted in pink. For both shallow and deep trefoils pknot shows a sigmoidal dependence on Q and there is a non-negligible probability for knotting and folding to occur concomitantly. For the more complex knot type knotting occurs in highly native-like conformations (Q > 0.8). pknot is the fraction of knotted conformations in very large ensembles of conformations (with fraction of native contacts Q or folding probability pfold) that are extracted from an equilibrium distribution at the temperature of interest. Details on the calculation of pfold can be found in [25].

Mentions: The folding probability, pfold (i.e. the probability that a conformation folds before it unfolds), measures how kinetically close a conformation is from the native one [87]. The stage of the folding process at which knotting is more likely to occur can be inferred with high accuracy from the dependence of the knotting probability, pknot, on the reaction coordinate pfold[25]. We found that knotting of our shallow trefoil knot occurs exceedingly late in folding, in conformations with pknot > 0.7 (Fig. 4a). An alternative, less computationally expensive measure of knotting progress, often used in off-lattice simulations, employs the fraction of native contacts, Q. It should be stressed that Q probes any knotted topology (including malformed knots) while pfold probes mostly natively knotted topologies. Accordingly, the knotting probability is always higher when folding progress is monitored with Q. Indeed, for the knot 31, pknot shows a sigmoidal dependence on Q at Tm, increasing sharply from ~ 0 to ~ 0.5 when Q = 0.5 [84] (Fig. 4b). A qualitatively similar behavior was reported in [85] for protein 2ouf, which also contains a shallow trefoil. However, for the knot 52 the threading step occurs much later, when the fraction of native contacts is larger than 0.9 [18] (Fig. 4b). This different timing for the knotting step is due to the larger knotting loop of the knot 52 (representing 60% of the chain length against 24% for the knot 31) that must form earlier and be in place for threading to occur. Therefore, independently of how folding is probed, and which model representation is adopted, results obtained so far by different groups [20,21,25], including experimental ones [86,88,89], point to a mechanism where the knotting step occurs late to very late during folding.


Knotted proteins: A tangled tale of Structural Biology.

Faísca PF - Comput Struct Biotechnol J (2015)

Knotting probability pknot, as a function of the folding probability, pfold (a) and as a function of fraction of formed native contacts, Q (b) in three lattice Go proteins: a shallow trefoil knot, a deep trefoil obtained from the first by extending the knot tails, and a shallow 52 knot. In the three dimensional structures the knotted core is highlighted. The three model systems fold with a thermodynamic two-state transition (data not shown) and the transition state ensemble comprises conformations in the region highlighted in pink. For both shallow and deep trefoils pknot shows a sigmoidal dependence on Q and there is a non-negligible probability for knotting and folding to occur concomitantly. For the more complex knot type knotting occurs in highly native-like conformations (Q > 0.8). pknot is the fraction of knotted conformations in very large ensembles of conformations (with fraction of native contacts Q or folding probability pfold) that are extracted from an equilibrium distribution at the temperature of interest. Details on the calculation of pfold can be found in [25].
© Copyright Policy - CC BY
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4556803&req=5

f0020: Knotting probability pknot, as a function of the folding probability, pfold (a) and as a function of fraction of formed native contacts, Q (b) in three lattice Go proteins: a shallow trefoil knot, a deep trefoil obtained from the first by extending the knot tails, and a shallow 52 knot. In the three dimensional structures the knotted core is highlighted. The three model systems fold with a thermodynamic two-state transition (data not shown) and the transition state ensemble comprises conformations in the region highlighted in pink. For both shallow and deep trefoils pknot shows a sigmoidal dependence on Q and there is a non-negligible probability for knotting and folding to occur concomitantly. For the more complex knot type knotting occurs in highly native-like conformations (Q > 0.8). pknot is the fraction of knotted conformations in very large ensembles of conformations (with fraction of native contacts Q or folding probability pfold) that are extracted from an equilibrium distribution at the temperature of interest. Details on the calculation of pfold can be found in [25].
Mentions: The folding probability, pfold (i.e. the probability that a conformation folds before it unfolds), measures how kinetically close a conformation is from the native one [87]. The stage of the folding process at which knotting is more likely to occur can be inferred with high accuracy from the dependence of the knotting probability, pknot, on the reaction coordinate pfold[25]. We found that knotting of our shallow trefoil knot occurs exceedingly late in folding, in conformations with pknot > 0.7 (Fig. 4a). An alternative, less computationally expensive measure of knotting progress, often used in off-lattice simulations, employs the fraction of native contacts, Q. It should be stressed that Q probes any knotted topology (including malformed knots) while pfold probes mostly natively knotted topologies. Accordingly, the knotting probability is always higher when folding progress is monitored with Q. Indeed, for the knot 31, pknot shows a sigmoidal dependence on Q at Tm, increasing sharply from ~ 0 to ~ 0.5 when Q = 0.5 [84] (Fig. 4b). A qualitatively similar behavior was reported in [85] for protein 2ouf, which also contains a shallow trefoil. However, for the knot 52 the threading step occurs much later, when the fraction of native contacts is larger than 0.9 [18] (Fig. 4b). This different timing for the knotting step is due to the larger knotting loop of the knot 52 (representing 60% of the chain length against 24% for the knot 31) that must form earlier and be in place for threading to occur. Therefore, independently of how folding is probed, and which model representation is adopted, results obtained so far by different groups [20,21,25], including experimental ones [86,88,89], point to a mechanism where the knotting step occurs late to very late during folding.

Bottom Line: Knotted proteins have their native structures arranged in the form of an open knot.Molecular simulations have been playing a fundamental role in this endeavor, and early computational predictions about the knotting mechanism have just been confirmed in wet lab experiments.Here we review a collection of simulation results that allow outlining the current status of the field of knotted proteins, and discuss directions for future research.

View Article: PubMed Central - PubMed

Affiliation: Departament of Physics and BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa, Portugal.

ABSTRACT
Knotted proteins have their native structures arranged in the form of an open knot. In the last ten years researchers have been making significant efforts to reveal their folding mechanism and understand which functional advantage(s) knots convey to their carriers. Molecular simulations have been playing a fundamental role in this endeavor, and early computational predictions about the knotting mechanism have just been confirmed in wet lab experiments. Here we review a collection of simulation results that allow outlining the current status of the field of knotted proteins, and discuss directions for future research.

No MeSH data available.


Related in: MedlinePlus