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Interplay between secondary and tertiary structure formation in protein folding cooperativity.

Bereau T, Bachmann M, Deserno M - J. Am. Chem. Soc. (2010)

Bottom Line: A microcanonical analysis, where the energy is the natural variable, has proved to be better suited than its canonical counterpart to unambiguously characterize the nature of the transition.The method has been applied to three helical peptides: a short helix shows sharp features of a two-state folder, while a longer helix and a three-helix bundle exhibit downhill and two-state transitions, respectively.Extending the results of lattice simulations and theoretical models, we have found that it is the interplay between secondary structure and the loss of non-native tertiary contacts that determines the nature of the transition.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.

ABSTRACT
Protein folding cooperativity is defined by the nature of the finite-size thermodynamic transition exhibited upon folding: two-state transitions show a free-energy barrier between the folded and unfolded ensembles, while downhill folding is barrierless. A microcanonical analysis, where the energy is the natural variable, has proved to be better suited than its canonical counterpart to unambiguously characterize the nature of the transition. Replica-exchange molecular dynamics simulations of a high-resolution coarse-grained model allow for the accurate evaluation of the density of states in order to extract precise thermodynamic information and measure its impact on structural features. The method has been applied to three helical peptides: a short helix shows sharp features of a two-state folder, while a longer helix and a three-helix bundle exhibit downhill and two-state transitions, respectively. Extending the results of lattice simulations and theoretical models, we have found that it is the interplay between secondary structure and the loss of non-native tertiary contacts that determines the nature of the transition.

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Results for (AAQAA)15. (a) ΔS(E). (b) Radius of gyration Rg(E). (c) Rates of H-bond and side-chain energies dEhb/dE and dEsc/dE. Horizontal arrows indicate where most of the secondary structure forms and where non-native tertiary contacts dissolve. The vertical line marks the transition point.
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fig2: Results for (AAQAA)15. (a) ΔS(E). (b) Radius of gyration Rg(E). (c) Rates of H-bond and side-chain energies dEhb/dE and dEsc/dE. Horizontal arrows indicate where most of the secondary structure forms and where non-native tertiary contacts dissolve. The vertical line marks the transition point.

Mentions: Elongating the sequence to (AAQAA)15 led to a qualitative change in the folding mechanism. The ground state again forms a single α-helix, but the transition is now continuous: as shown in Figure 2a and Figure S2 in the Supporting Information, there is a single transition point, and the latent heat is zero. The radius of gyration (Figure 2b) features a sharp minimum above the transition point, indicative of chain collapse into “maximally compact non-native states”.(13) Upon a further decrease in the energy, the chain reorganizes from such non-native states into the helical state. In doing so, the rate of tertiary contact formation dEsc/dE dips below zero (Figure 2c), so there is an energetic penalty associated with tertiary rearrangements. Hydrogen-bond formation occurs over a large energetic interval, as indicated by the broad maximum in dEhb/dE. The absence of any two-state signal is consistent with theoretical models of the helix−coil transition:(14) the energetic cost of breaking a hydrogen bond is outweighed by the conformational entropy gained. Further analysis indicates two helices on average at the transition point.


Interplay between secondary and tertiary structure formation in protein folding cooperativity.

Bereau T, Bachmann M, Deserno M - J. Am. Chem. Soc. (2010)

Results for (AAQAA)15. (a) ΔS(E). (b) Radius of gyration Rg(E). (c) Rates of H-bond and side-chain energies dEhb/dE and dEsc/dE. Horizontal arrows indicate where most of the secondary structure forms and where non-native tertiary contacts dissolve. The vertical line marks the transition point.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2944381&req=5

fig2: Results for (AAQAA)15. (a) ΔS(E). (b) Radius of gyration Rg(E). (c) Rates of H-bond and side-chain energies dEhb/dE and dEsc/dE. Horizontal arrows indicate where most of the secondary structure forms and where non-native tertiary contacts dissolve. The vertical line marks the transition point.
Mentions: Elongating the sequence to (AAQAA)15 led to a qualitative change in the folding mechanism. The ground state again forms a single α-helix, but the transition is now continuous: as shown in Figure 2a and Figure S2 in the Supporting Information, there is a single transition point, and the latent heat is zero. The radius of gyration (Figure 2b) features a sharp minimum above the transition point, indicative of chain collapse into “maximally compact non-native states”.(13) Upon a further decrease in the energy, the chain reorganizes from such non-native states into the helical state. In doing so, the rate of tertiary contact formation dEsc/dE dips below zero (Figure 2c), so there is an energetic penalty associated with tertiary rearrangements. Hydrogen-bond formation occurs over a large energetic interval, as indicated by the broad maximum in dEhb/dE. The absence of any two-state signal is consistent with theoretical models of the helix−coil transition:(14) the energetic cost of breaking a hydrogen bond is outweighed by the conformational entropy gained. Further analysis indicates two helices on average at the transition point.

Bottom Line: A microcanonical analysis, where the energy is the natural variable, has proved to be better suited than its canonical counterpart to unambiguously characterize the nature of the transition.The method has been applied to three helical peptides: a short helix shows sharp features of a two-state folder, while a longer helix and a three-helix bundle exhibit downhill and two-state transitions, respectively.Extending the results of lattice simulations and theoretical models, we have found that it is the interplay between secondary structure and the loss of non-native tertiary contacts that determines the nature of the transition.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.

ABSTRACT
Protein folding cooperativity is defined by the nature of the finite-size thermodynamic transition exhibited upon folding: two-state transitions show a free-energy barrier between the folded and unfolded ensembles, while downhill folding is barrierless. A microcanonical analysis, where the energy is the natural variable, has proved to be better suited than its canonical counterpart to unambiguously characterize the nature of the transition. Replica-exchange molecular dynamics simulations of a high-resolution coarse-grained model allow for the accurate evaluation of the density of states in order to extract precise thermodynamic information and measure its impact on structural features. The method has been applied to three helical peptides: a short helix shows sharp features of a two-state folder, while a longer helix and a three-helix bundle exhibit downhill and two-state transitions, respectively. Extending the results of lattice simulations and theoretical models, we have found that it is the interplay between secondary structure and the loss of non-native tertiary contacts that determines the nature of the transition.

Show MeSH