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Generation of a flexible loop structural ensemble and its application to induced-fit structural changes following ligand binding

View Article: PubMed Central - PubMed

ABSTRACT

Molecular recognition is often mediated by flexible loops that have widely fluctuating structures and are sometimes disordered, but that form particular complex structures following ligand binding. In fact, many loop structures found in the PDB database are too flexible to be determined precisely. A new loop modeling method was therefore developed using force-biased multicanonical molecular dynamics with the implicit solvent model to generate an ensemble of putative loop structures with low free energy values. The method was then used to create ensembles for several flexible loops that were compared with the corresponding NMR and X-ray structures. The induced-fit structural change of dihydrofolate reductase (DHFR) was also predicted from a structural ensemble of ligand-free M20 loop conformations and successive docking simulations.

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(A) PCA of the canonical ensemble of Loop R8 at 300 K, projected on the first and second principal axes. The blue, cyan, green, orange and red dots correspond to structures of the R8α cluster, the R8β cluster, the R8γ cluster, the 32 NMR structures (2AAS) and a crystal structure (8RAT), respectively. The filled black circle, filled black triangle and filled black square correspond to center structures of the R8α, R8β and R8γ clusters, respectively. (B) PCA for the canonical ensemble of Loop R12 at 300 K, projected on the first and second principal axes. The blue, cyan, orange, and red dots correspond to structures of the R12α cluster, the R12β cluster, 32 structures of NMR (2AAS), and a crystal structure (8RAT), respectively. The filled black circles and filled black triangles correspond to center structures of the R12α and R12β clusters, respectively.
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f3-2_1: (A) PCA of the canonical ensemble of Loop R8 at 300 K, projected on the first and second principal axes. The blue, cyan, green, orange and red dots correspond to structures of the R8α cluster, the R8β cluster, the R8γ cluster, the 32 NMR structures (2AAS) and a crystal structure (8RAT), respectively. The filled black circle, filled black triangle and filled black square correspond to center structures of the R8α, R8β and R8γ clusters, respectively. (B) PCA for the canonical ensemble of Loop R12 at 300 K, projected on the first and second principal axes. The blue, cyan, orange, and red dots correspond to structures of the R12α cluster, the R12β cluster, 32 structures of NMR (2AAS), and a crystal structure (8RAT), respectively. The filled black circles and filled black triangles correspond to center structures of the R12α and R12β clusters, respectively.

Mentions: Figure 3A shows the results of the PCA analysis projected onto two-dimensional (2D) space with the first and second principle axes for the Loop R8 ensemble with the NMR (PDB code, 2AAS) and X-ray crystal (8RAT) structures. The contributions from the first, second, third, fourth and fifth axes correspond to 64.2%, 19.9%, 4.9%, 3.4% and 1.5% of the total components, respectively. Three different clusters, ‘R8α’, ‘R8β’ and ‘R8γ’, were clearly observed, and the major cluster, R8α, coincided with the NMR and X-ray crystal structures with <RMSDn> = 0.93 Å and RMSDx=1.20 Å, as shown in Table 1. Here, <RMSDn> is the average of the 32 RMSD values, each of which is the RMSD of the heavy atoms in Loop R8 between a current model structure and one of the 32 NMR structures (2AAS). RMSDx represents the RMSD value of the heavy atoms in Loop R8 between the X-ray crystal structure (8RAT) and the modeled structure.


Generation of a flexible loop structural ensemble and its application to induced-fit structural changes following ligand binding
(A) PCA of the canonical ensemble of Loop R8 at 300 K, projected on the first and second principal axes. The blue, cyan, green, orange and red dots correspond to structures of the R8α cluster, the R8β cluster, the R8γ cluster, the 32 NMR structures (2AAS) and a crystal structure (8RAT), respectively. The filled black circle, filled black triangle and filled black square correspond to center structures of the R8α, R8β and R8γ clusters, respectively. (B) PCA for the canonical ensemble of Loop R12 at 300 K, projected on the first and second principal axes. The blue, cyan, orange, and red dots correspond to structures of the R12α cluster, the R12β cluster, 32 structures of NMR (2AAS), and a crystal structure (8RAT), respectively. The filled black circles and filled black triangles correspond to center structures of the R12α and R12β clusters, respectively.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036648&req=5

f3-2_1: (A) PCA of the canonical ensemble of Loop R8 at 300 K, projected on the first and second principal axes. The blue, cyan, green, orange and red dots correspond to structures of the R8α cluster, the R8β cluster, the R8γ cluster, the 32 NMR structures (2AAS) and a crystal structure (8RAT), respectively. The filled black circle, filled black triangle and filled black square correspond to center structures of the R8α, R8β and R8γ clusters, respectively. (B) PCA for the canonical ensemble of Loop R12 at 300 K, projected on the first and second principal axes. The blue, cyan, orange, and red dots correspond to structures of the R12α cluster, the R12β cluster, 32 structures of NMR (2AAS), and a crystal structure (8RAT), respectively. The filled black circles and filled black triangles correspond to center structures of the R12α and R12β clusters, respectively.
Mentions: Figure 3A shows the results of the PCA analysis projected onto two-dimensional (2D) space with the first and second principle axes for the Loop R8 ensemble with the NMR (PDB code, 2AAS) and X-ray crystal (8RAT) structures. The contributions from the first, second, third, fourth and fifth axes correspond to 64.2%, 19.9%, 4.9%, 3.4% and 1.5% of the total components, respectively. Three different clusters, ‘R8α’, ‘R8β’ and ‘R8γ’, were clearly observed, and the major cluster, R8α, coincided with the NMR and X-ray crystal structures with <RMSDn> = 0.93 Å and RMSDx=1.20 Å, as shown in Table 1. Here, <RMSDn> is the average of the 32 RMSD values, each of which is the RMSD of the heavy atoms in Loop R8 between a current model structure and one of the 32 NMR structures (2AAS). RMSDx represents the RMSD value of the heavy atoms in Loop R8 between the X-ray crystal structure (8RAT) and the modeled structure.

View Article: PubMed Central - PubMed

ABSTRACT

Molecular recognition is often mediated by flexible loops that have widely fluctuating structures and are sometimes disordered, but that form particular complex structures following ligand binding. In fact, many loop structures found in the PDB database are too flexible to be determined precisely. A new loop modeling method was therefore developed using force-biased multicanonical molecular dynamics with the implicit solvent model to generate an ensemble of putative loop structures with low free energy values. The method was then used to create ensembles for several flexible loops that were compared with the corresponding NMR and X-ray structures. The induced-fit structural change of dihydrofolate reductase (DHFR) was also predicted from a structural ensemble of ligand-free M20 loop conformations and successive docking simulations.

No MeSH data available.


Related in: MedlinePlus