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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.


Cα-RMSDs from the X-ray structure as a function of time. Cα-RMSD trajectories of ten unfolding simulations (D1–D10) and of a control simulation at 300 K are shown. Each trajectory is indicated in different color.
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f2-3_1: Cα-RMSDs from the X-ray structure as a function of time. Cα-RMSD trajectories of ten unfolding simulations (D1–D10) and of a control simulation at 300 K are shown. Each trajectory is indicated in different color.

Mentions: Trajectories of Cα-RMSD from the X-ray structure for the ten molecular dynamics simulations at 498 K show that barnase was progressively unfolded in various ways (Fig. 2). Conformations at 3 ns end points of the ten unfolding trajectories were largely different from the native structure and also different from each other (Fig. 3). Properties of these final structures are shown in Table 1. Seven of the ten unfolding trajectories reached Cα-RMSD of more than 10 angstrom. Less than 20% of the native hydrogen bonds were retained at 3 ns end points of 8 trajectories. These results demonstrate that various unfolding pathways of barnase were sampled in our simulations. Detailed analyses of persistence or loss of specific structural elements are described below.


Retention of local conformational compactness in unfolding of barnase; Contribution of end-to-end interactions within quasi-modules
Cα-RMSDs from the X-ray structure as a function of time. Cα-RMSD trajectories of ten unfolding simulations (D1–D10) and of a control simulation at 300 K are shown. Each trajectory is indicated in different color.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC5036653&req=5

f2-3_1: Cα-RMSDs from the X-ray structure as a function of time. Cα-RMSD trajectories of ten unfolding simulations (D1–D10) and of a control simulation at 300 K are shown. Each trajectory is indicated in different color.
Mentions: Trajectories of Cα-RMSD from the X-ray structure for the ten molecular dynamics simulations at 498 K show that barnase was progressively unfolded in various ways (Fig. 2). Conformations at 3 ns end points of the ten unfolding trajectories were largely different from the native structure and also different from each other (Fig. 3). Properties of these final structures are shown in Table 1. Seven of the ten unfolding trajectories reached Cα-RMSD of more than 10 angstrom. Less than 20% of the native hydrogen bonds were retained at 3 ns end points of 8 trajectories. These results demonstrate that various unfolding pathways of barnase were sampled in our simulations. Detailed analyses of persistence or loss of specific structural elements are described below.

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.