Limits...
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.

Show MeSH
Results for the three-helix bundle α3D. (a) ΔS(E). (b) Radius of gyration Rg(E). (c) Rates of H-bond and side-chain energies dEhb/dE and  dEsc/dE.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2944381&req=5

fig3: Results for the three-helix bundle α3D. (a) ΔS(E). (b) Radius of gyration Rg(E). (c) Rates of H-bond and side-chain energies dEhb/dE and  dEsc/dE.

Mentions: While of similar length, the 73 amino acid de novo three-helix bundle α3D (PDB entry 2A3D)(15) does show a discontinuous transition (Figure 3a). Representative conformations sampled in the two coexisting ensembles stand as good proxies of the ground and unfolded states, unlike the case of the downhill-folding transition of (AAQAA)15. The radius of gyration again shows a minimum above the transition (Figure 3b), and folding once more starts from maximally compact non-native states. Notably, secondary structure formation and the loss of non-native tertiary contacts (Figure 3c) are sharp and predominantly localized within the coexistence region. The three helices form inside the same energetic interval because of the interhelical cooperativity imprinted in the sequence.(16) Chain compaction is due to strong side chain−side chain interactions.


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

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

Results for the three-helix bundle α3D. (a) ΔS(E). (b) Radius of gyration Rg(E). (c) Rates of H-bond and side-chain energies dEhb/dE and  dEsc/dE.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Results for the three-helix bundle α3D. (a) ΔS(E). (b) Radius of gyration Rg(E). (c) Rates of H-bond and side-chain energies dEhb/dE and  dEsc/dE.
Mentions: While of similar length, the 73 amino acid de novo three-helix bundle α3D (PDB entry 2A3D)(15) does show a discontinuous transition (Figure 3a). Representative conformations sampled in the two coexisting ensembles stand as good proxies of the ground and unfolded states, unlike the case of the downhill-folding transition of (AAQAA)15. The radius of gyration again shows a minimum above the transition (Figure 3b), and folding once more starts from maximally compact non-native states. Notably, secondary structure formation and the loss of non-native tertiary contacts (Figure 3c) are sharp and predominantly localized within the coexistence region. The three helices form inside the same energetic interval because of the interhelical cooperativity imprinted in the sequence.(16) Chain compaction is due to strong side chain−side chain interactions.

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