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

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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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PCA of the ensemble of Loop M20 in DHFR at 300 K, projected on the first and second principal axes. The blue, cyan, green and yellow dots correspond to the M20α, M20β, M20γ and M20δ clusters, respectively. The filled red circles, open red circles and red circles with a cross correspond to crystal structures of the closed form with NADP+ (PDB code, 1RX2), the open form with NADP+ (1RA2) and the occluded form without NADP+ (1RX5), respectively. The other 34 crystal structures are indicated by filled orange circles.
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f5-2_1: PCA of the ensemble of Loop M20 in DHFR at 300 K, projected on the first and second principal axes. The blue, cyan, green and yellow dots correspond to the M20α, M20β, M20γ and M20δ clusters, respectively. The filled red circles, open red circles and red circles with a cross correspond to crystal structures of the closed form with NADP+ (PDB code, 1RX2), the open form with NADP+ (1RA2) and the occluded form without NADP+ (1RX5), respectively. The other 34 crystal structures are indicated by filled orange circles.

Mentions: From the canonical ensemble of Loop M20 at 300 K, 2000 structures were randomly selected, and the structures in the ensemble were subjected to PCA with several crystal structures. Figure 5 shows the results of the PCA projected onto 2D space with the first and second principal axes. The contributions from the first, second, third, fourth and fifth axes correspond to 46.1%, 16.2%, 8.7%, 5.6% and 4.8% of all the components, respectively. Following Ward’s method, the ensemble was separated by the four clusters M20α, M20β, M20γ and M20δ, as shown in Fig. 5. The probability of the conformations in the M20α, M20β, M20γ and M20δ clusters is 65.4%, 21.3%, 10.3% and 3.1%, respectively.


Generation of a flexible loop structural ensemble and its application to induced-fit structural changes following ligand binding
PCA of the ensemble of Loop M20 in DHFR at 300 K, projected on the first and second principal axes. The blue, cyan, green and yellow dots correspond to the M20α, M20β, M20γ and M20δ clusters, respectively. The filled red circles, open red circles and red circles with a cross correspond to crystal structures of the closed form with NADP+ (PDB code, 1RX2), the open form with NADP+ (1RA2) and the occluded form without NADP+ (1RX5), respectively. The other 34 crystal structures are indicated by filled orange circles.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC5036648&req=5

f5-2_1: PCA of the ensemble of Loop M20 in DHFR at 300 K, projected on the first and second principal axes. The blue, cyan, green and yellow dots correspond to the M20α, M20β, M20γ and M20δ clusters, respectively. The filled red circles, open red circles and red circles with a cross correspond to crystal structures of the closed form with NADP+ (PDB code, 1RX2), the open form with NADP+ (1RA2) and the occluded form without NADP+ (1RX5), respectively. The other 34 crystal structures are indicated by filled orange circles.
Mentions: From the canonical ensemble of Loop M20 at 300 K, 2000 structures were randomly selected, and the structures in the ensemble were subjected to PCA with several crystal structures. Figure 5 shows the results of the PCA projected onto 2D space with the first and second principal axes. The contributions from the first, second, third, fourth and fifth axes correspond to 46.1%, 16.2%, 8.7%, 5.6% and 4.8% of all the components, respectively. Following Ward’s method, the ensemble was separated by the four clusters M20α, M20β, M20γ and M20δ, as shown in Fig. 5. The probability of the conformations in the M20α, M20β, M20γ and M20δ clusters is 65.4%, 21.3%, 10.3% and 3.1%, respectively.

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