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Retention of local conformational compactness in unfolding of barnase; Contribution of end-to-end interactions within quasi-modules

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ABSTRACT

To understand how protein reduces the conformational space to be searched for the native structure, it is crucial to characterize ensembles of conformations on the way of folding processes, in particular ensembles of relatively long-range structures connecting between an extensively unfolded state and a state with a native-like overall chain topology. To analyze such intermediate conformations, we performed multiple unfolding molecular dynamics simulations of barnase at 498K. Some short-range structures such as part of helix and turn were well sustained while most of the secondary structures and the hydrophobic cores were eventually lost, which is consistent with the results by other experimental and computational studies. The most important novel findings were persistence of long-range relatively compact substructures, which was captured by exploiting the concept of module. Module is originally introduced to describe the hierarchical structure of a globular protein in the native state. Modules are conceptually such relatively compact substructures that are resulted from partitioning the native structure of a globular protein completely into several contiguous segments with the least extended conformations. We applied this concept of module to detect a possible hierarchical structure of each snapshot structure in unfolding processes as well. Along with this conceptual extension, such detected relatively compact substructures are named quasi-modules. We found almost perfect persistence of quasi-module boundaries that are positioned close to the native module boundaries throughout the unfolding trajectories. Relatively compact conformations of the quasi-modules seemed to be retained mainly by hydrophobic interactions formed between residues located at both terminal regions within each module. From these results, we propose a hypothesis that hierarchical folding with the early formation of quasi-modules effectively reduces search space for the native structure.

No MeSH data available.


A representative unfolded structure of barnase. The structure at 3 ns end point of the trajectory D4 (bottom) is shown with the native structure of barnase (top). Color scheme is the same as that of Figure 1(c).
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f11-3_1: A representative unfolded structure of barnase. The structure at 3 ns end point of the trajectory D4 (bottom) is shown with the native structure of barnase (top). Color scheme is the same as that of Figure 1(c).

Mentions: Our unfolding simulations of barnase were basically the same in the simulation protocol as that of Daggett’s group11,13 although using different software. In addition to the observation of the same residual local structures mentioned above, they observed persistence of roughly native-like chain topology in the unfolding simulations. On the other hand, more diverse conformations not necessarily possessing native-like chain topology were sampled in our simulations (see Fig. 3 and 11). This is probably because a larger number of independent unfolding simulations were performed in our study. Surprisingly, even in such more unfolded conformations, we observed with high probability some hierarchical structure composed of quasi-modules (relatively long-range compact segments) corresponding in sequence position and compactness to the native modules (see Fig. 10 and 11). While Daggett’s group observed a segment of residues 25–55, which closely corresponds to module M2, behaving as a semiautonomous unit independent of the rest of barnase11,13, we observed all of the segments corresponding to the native modules behaving relatively independent of each other in our simulations. Compactness of quasi-modules seems to be maintained by hydrophobic interactions between terminal regions within each module because relatively high persistency of native hydrophobic contacts was observed at such regions.


Retention of local conformational compactness in unfolding of barnase; Contribution of end-to-end interactions within quasi-modules
A representative unfolded structure of barnase. The structure at 3 ns end point of the trajectory D4 (bottom) is shown with the native structure of barnase (top). Color scheme is the same as that of Figure 1(c).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036653&req=5

f11-3_1: A representative unfolded structure of barnase. The structure at 3 ns end point of the trajectory D4 (bottom) is shown with the native structure of barnase (top). Color scheme is the same as that of Figure 1(c).
Mentions: Our unfolding simulations of barnase were basically the same in the simulation protocol as that of Daggett’s group11,13 although using different software. In addition to the observation of the same residual local structures mentioned above, they observed persistence of roughly native-like chain topology in the unfolding simulations. On the other hand, more diverse conformations not necessarily possessing native-like chain topology were sampled in our simulations (see Fig. 3 and 11). This is probably because a larger number of independent unfolding simulations were performed in our study. Surprisingly, even in such more unfolded conformations, we observed with high probability some hierarchical structure composed of quasi-modules (relatively long-range compact segments) corresponding in sequence position and compactness to the native modules (see Fig. 10 and 11). While Daggett’s group observed a segment of residues 25–55, which closely corresponds to module M2, behaving as a semiautonomous unit independent of the rest of barnase11,13, we observed all of the segments corresponding to the native modules behaving relatively independent of each other in our simulations. Compactness of quasi-modules seems to be maintained by hydrophobic interactions between terminal regions within each module because relatively high persistency of native hydrophobic contacts was observed at such regions.

View Article: PubMed Central - PubMed

ABSTRACT

To understand how protein reduces the conformational space to be searched for the native structure, it is crucial to characterize ensembles of conformations on the way of folding processes, in particular ensembles of relatively long-range structures connecting between an extensively unfolded state and a state with a native-like overall chain topology. To analyze such intermediate conformations, we performed multiple unfolding molecular dynamics simulations of barnase at 498K. Some short-range structures such as part of helix and turn were well sustained while most of the secondary structures and the hydrophobic cores were eventually lost, which is consistent with the results by other experimental and computational studies. The most important novel findings were persistence of long-range relatively compact substructures, which was captured by exploiting the concept of module. Module is originally introduced to describe the hierarchical structure of a globular protein in the native state. Modules are conceptually such relatively compact substructures that are resulted from partitioning the native structure of a globular protein completely into several contiguous segments with the least extended conformations. We applied this concept of module to detect a possible hierarchical structure of each snapshot structure in unfolding processes as well. Along with this conceptual extension, such detected relatively compact substructures are named quasi-modules. We found almost perfect persistence of quasi-module boundaries that are positioned close to the native module boundaries throughout the unfolding trajectories. Relatively compact conformations of the quasi-modules seemed to be retained mainly by hydrophobic interactions formed between residues located at both terminal regions within each module. From these results, we propose a hypothesis that hierarchical folding with the early formation of quasi-modules effectively reduces search space for the native structure.

No MeSH data available.