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

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.


Representative conformations of segments corresponding to modules M3 and M5, which are picked up from the most unfolded ensemble (the bin of Q=0.125). The native structures of the modules are also shown for comparison. A hydrogen bond and a cluster of hydrophobic residues are shown by a red broken line and an orange broken circle, respectively.
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f10-3_1: Representative conformations of segments corresponding to modules M3 and M5, which are picked up from the most unfolded ensemble (the bin of Q=0.125). The native structures of the modules are also shown for comparison. A hydrogen bond and a cluster of hydrophobic residues are shown by a red broken line and an orange broken circle, respectively.

Mentions: We further focused on native contacts formed between only hydrophobic residues (Fig. 9a–d top right triangle halves). We found relatively high persistency of hydrophobic contacts between terminal regions within each module except for the N-terminal module M1 and the C-terminal module M6. Figure 10 shows representative conformations of segments corresponding to modules M3 and M5, which are picked up from the most unfolded ensemble (the bin of Q=0.125). It seems that a cluster of hydrophobic residues formed between terminal regions within each module is a major factor to retain native-like compactness of modules.


Retention of local conformational compactness in unfolding of barnase; Contribution of end-to-end interactions within quasi-modules
Representative conformations of segments corresponding to modules M3 and M5, which are picked up from the most unfolded ensemble (the bin of Q=0.125). The native structures of the modules are also shown for comparison. A hydrogen bond and a cluster of hydrophobic residues are shown by a red broken line and an orange broken circle, respectively.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036653&req=5

f10-3_1: Representative conformations of segments corresponding to modules M3 and M5, which are picked up from the most unfolded ensemble (the bin of Q=0.125). The native structures of the modules are also shown for comparison. A hydrogen bond and a cluster of hydrophobic residues are shown by a red broken line and an orange broken circle, respectively.
Mentions: We further focused on native contacts formed between only hydrophobic residues (Fig. 9a–d top right triangle halves). We found relatively high persistency of hydrophobic contacts between terminal regions within each module except for the N-terminal module M1 and the C-terminal module M6. Figure 10 shows representative conformations of segments corresponding to modules M3 and M5, which are picked up from the most unfolded ensemble (the bin of Q=0.125). It seems that a cluster of hydrophobic residues formed between terminal regions within each module is a major factor to retain native-like compactness of modules.

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.