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Native contact density and nonnative hydrophobic effects in the folding of bacterial immunity proteins.

Chen T, Chan HS - PLoS Comput. Biol. (2015)

Bottom Line: Hydrophobic residues identified by published experiments to be involved in nonnative interactions during Im7 folding are found to participate in the strongest nonnative contacts in this model.Our simulation suggests further that nonnative effects in Im7 are facilitated by a lower local native contact density relative to that of Im9.In a one-dimensional diffusion picture of Im7 folding with a coordinate- and stability-dependent diffusion coefficient, a significant chevron rollover is consistent with a diffusion coefficient that depends strongly on native stability at the conformational position of the folding intermediate.

View Article: PubMed Central - PubMed

Affiliation: Departments of Biochemistry, of Molecular Genetics, and of Physics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

ABSTRACT
The bacterial colicin-immunity proteins Im7 and Im9 fold by different mechanisms. Experimentally, at pH 7.0 and 10°C, Im7 folds in a three-state manner via an intermediate but Im9 folding is two-state-like. Accordingly, Im7 exhibits a chevron rollover, whereas the chevron arm for Im9 folding is linear. Here we address the biophysical basis of their different behaviors by using native-centric models with and without additional transferrable, sequence-dependent energies. The Im7 chevron rollover is not captured by either a pure native-centric model or a model augmented by nonnative hydrophobic interactions with a uniform strength irrespective of residue type. By contrast, a more realistic nonnative interaction scheme that accounts for the difference in hydrophobicity among residues leads simultaneously to a chevron rollover for Im7 and an essentially linear folding chevron arm for Im9. Hydrophobic residues identified by published experiments to be involved in nonnative interactions during Im7 folding are found to participate in the strongest nonnative contacts in this model. Thus our observations support the experimental perspective that the Im7 folding intermediate is largely underpinned by nonnative interactions involving large hydrophobics. Our simulation suggests further that nonnative effects in Im7 are facilitated by a lower local native contact density relative to that of Im9. In a one-dimensional diffusion picture of Im7 folding with a coordinate- and stability-dependent diffusion coefficient, a significant chevron rollover is consistent with a diffusion coefficient that depends strongly on native stability at the conformational position of the folding intermediate.

No MeSH data available.


Transiently trapped conformations.(A, B) Examples of folding trajectories of Im7 (A) and Im9 (B) simulated using the db+MJhϕ model under zero-denaturant conditions (ϵ/kBT = 1.48 and 1.39 respectively). Transiently trapped conformations with Q ≈ 0.8–0.9 are observed for the Im7 trajectory [highlighted by horizontal gray shading in (A)] but not for the Im9 trajectory in (B). (C, D) Kinetic FP profiles [59] in the db, db+hϕ, and db+MJhϕ models (same line styles as Fig 1) for Im7 (C) and Im9 (D). The approximate range of Q values for the conformations constituting the transiently trapped Im7 intermediate in the db+MJhϕ model is indicated by the vertical gray band in (C). The number of trajectories used to computed the kinetic FP profiles in the three models are, respectively, 1,600, 1,240, and 1,139 for Im7 and 1,600, 1,600, and 3,200 for Im9.
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pcbi.1004260.g004: Transiently trapped conformations.(A, B) Examples of folding trajectories of Im7 (A) and Im9 (B) simulated using the db+MJhϕ model under zero-denaturant conditions (ϵ/kBT = 1.48 and 1.39 respectively). Transiently trapped conformations with Q ≈ 0.8–0.9 are observed for the Im7 trajectory [highlighted by horizontal gray shading in (A)] but not for the Im9 trajectory in (B). (C, D) Kinetic FP profiles [59] in the db, db+hϕ, and db+MJhϕ models (same line styles as Fig 1) for Im7 (C) and Im9 (D). The approximate range of Q values for the conformations constituting the transiently trapped Im7 intermediate in the db+MJhϕ model is indicated by the vertical gray band in (C). The number of trajectories used to computed the kinetic FP profiles in the three models are, respectively, 1,600, 1,240, and 1,139 for Im7 and 1,600, 1,600, and 3,200 for Im9.

Mentions: The approximate linearity of native stability versus interaction strength ϵ/T (Fig 2B) allows ΔG/kBT to be used as a proxy for denaturant concentration [42] in model chevron plots. Fig 3 shows that the folding-arm rollover and lack thereof, respectively, in the experimental chevrons for Im7 and Im9 at pH 7.0 and 10°C [16, 18–20] is captured by the db+MJhϕ but not the db and db+hϕ models, suggesting that the Im7 rollover arises from the strong nonnative interactions among the large hydrophobic residues as modeled by db+MJhϕ (S1 Fig). The difference between Im7 and Im9 folding cannot be explained by native interactions alone (as in db) or the more generic nonnative hydrophobic effects in db+hϕ. The chevron rollover in the db+MJhϕ Im7 model is a consequence of transient yet long-lived trapped conformations at Q ≈ 0.85 (Fig 4A), which do not appear in Im9 folding under similarly strong folding conditions (Fig 4B).


Native contact density and nonnative hydrophobic effects in the folding of bacterial immunity proteins.

Chen T, Chan HS - PLoS Comput. Biol. (2015)

Transiently trapped conformations.(A, B) Examples of folding trajectories of Im7 (A) and Im9 (B) simulated using the db+MJhϕ model under zero-denaturant conditions (ϵ/kBT = 1.48 and 1.39 respectively). Transiently trapped conformations with Q ≈ 0.8–0.9 are observed for the Im7 trajectory [highlighted by horizontal gray shading in (A)] but not for the Im9 trajectory in (B). (C, D) Kinetic FP profiles [59] in the db, db+hϕ, and db+MJhϕ models (same line styles as Fig 1) for Im7 (C) and Im9 (D). The approximate range of Q values for the conformations constituting the transiently trapped Im7 intermediate in the db+MJhϕ model is indicated by the vertical gray band in (C). The number of trajectories used to computed the kinetic FP profiles in the three models are, respectively, 1,600, 1,240, and 1,139 for Im7 and 1,600, 1,600, and 3,200 for Im9.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4446218&req=5

pcbi.1004260.g004: Transiently trapped conformations.(A, B) Examples of folding trajectories of Im7 (A) and Im9 (B) simulated using the db+MJhϕ model under zero-denaturant conditions (ϵ/kBT = 1.48 and 1.39 respectively). Transiently trapped conformations with Q ≈ 0.8–0.9 are observed for the Im7 trajectory [highlighted by horizontal gray shading in (A)] but not for the Im9 trajectory in (B). (C, D) Kinetic FP profiles [59] in the db, db+hϕ, and db+MJhϕ models (same line styles as Fig 1) for Im7 (C) and Im9 (D). The approximate range of Q values for the conformations constituting the transiently trapped Im7 intermediate in the db+MJhϕ model is indicated by the vertical gray band in (C). The number of trajectories used to computed the kinetic FP profiles in the three models are, respectively, 1,600, 1,240, and 1,139 for Im7 and 1,600, 1,600, and 3,200 for Im9.
Mentions: The approximate linearity of native stability versus interaction strength ϵ/T (Fig 2B) allows ΔG/kBT to be used as a proxy for denaturant concentration [42] in model chevron plots. Fig 3 shows that the folding-arm rollover and lack thereof, respectively, in the experimental chevrons for Im7 and Im9 at pH 7.0 and 10°C [16, 18–20] is captured by the db+MJhϕ but not the db and db+hϕ models, suggesting that the Im7 rollover arises from the strong nonnative interactions among the large hydrophobic residues as modeled by db+MJhϕ (S1 Fig). The difference between Im7 and Im9 folding cannot be explained by native interactions alone (as in db) or the more generic nonnative hydrophobic effects in db+hϕ. The chevron rollover in the db+MJhϕ Im7 model is a consequence of transient yet long-lived trapped conformations at Q ≈ 0.85 (Fig 4A), which do not appear in Im9 folding under similarly strong folding conditions (Fig 4B).

Bottom Line: Hydrophobic residues identified by published experiments to be involved in nonnative interactions during Im7 folding are found to participate in the strongest nonnative contacts in this model.Our simulation suggests further that nonnative effects in Im7 are facilitated by a lower local native contact density relative to that of Im9.In a one-dimensional diffusion picture of Im7 folding with a coordinate- and stability-dependent diffusion coefficient, a significant chevron rollover is consistent with a diffusion coefficient that depends strongly on native stability at the conformational position of the folding intermediate.

View Article: PubMed Central - PubMed

Affiliation: Departments of Biochemistry, of Molecular Genetics, and of Physics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

ABSTRACT
The bacterial colicin-immunity proteins Im7 and Im9 fold by different mechanisms. Experimentally, at pH 7.0 and 10°C, Im7 folds in a three-state manner via an intermediate but Im9 folding is two-state-like. Accordingly, Im7 exhibits a chevron rollover, whereas the chevron arm for Im9 folding is linear. Here we address the biophysical basis of their different behaviors by using native-centric models with and without additional transferrable, sequence-dependent energies. The Im7 chevron rollover is not captured by either a pure native-centric model or a model augmented by nonnative hydrophobic interactions with a uniform strength irrespective of residue type. By contrast, a more realistic nonnative interaction scheme that accounts for the difference in hydrophobicity among residues leads simultaneously to a chevron rollover for Im7 and an essentially linear folding chevron arm for Im9. Hydrophobic residues identified by published experiments to be involved in nonnative interactions during Im7 folding are found to participate in the strongest nonnative contacts in this model. Thus our observations support the experimental perspective that the Im7 folding intermediate is largely underpinned by nonnative interactions involving large hydrophobics. Our simulation suggests further that nonnative effects in Im7 are facilitated by a lower local native contact density relative to that of Im9. In a one-dimensional diffusion picture of Im7 folding with a coordinate- and stability-dependent diffusion coefficient, a significant chevron rollover is consistent with a diffusion coefficient that depends strongly on native stability at the conformational position of the folding intermediate.

No MeSH data available.