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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.

No MeSH data available.


(A) The trajectory of the potential energy of Loop R8 as determined by the FBMcMD method with the GBSA model. (B) Energy distribution of the multicanonical ensemble (solid line). The dotted curve and dashed curve represent the canonical ensembles calculated by the re-weighting method at 300 K and 700 K, respectively.
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f2-2_1: (A) The trajectory of the potential energy of Loop R8 as determined by the FBMcMD method with the GBSA model. (B) Energy distribution of the multicanonical ensemble (solid line). The dotted curve and dashed curve represent the canonical ensembles calculated by the re-weighting method at 300 K and 700 K, respectively.

Mentions: The potential energy trajectory of a multicanonical simulation is shown in Fig. 2A for the 8-residue flexible loop system in RNase A designated as Loop R8 in Fig. 1. Loop R8 is composed of flexible loop residues 64 to 71, and 27 other surrounding residues. The potential energy was initially ca. −290 kcal/mol, and gradually increased to cover a wide energy range by random-walking in the energy space. Figure 2B shows the energy distribution of the multicanoni-cal ensemble for this flexible loop system obtained by the current FBMcMD method, with the energy distributions for the re-weighted canonical ensembles at 300 K and 700 K. The flat energy distribution in Fig. 2B indicates that the current method succeeded in generating the multicanonical ensemble.


Generation of a flexible loop structural ensemble and its application to induced-fit structural changes following ligand binding
(A) The trajectory of the potential energy of Loop R8 as determined by the FBMcMD method with the GBSA model. (B) Energy distribution of the multicanonical ensemble (solid line). The dotted curve and dashed curve represent the canonical ensembles calculated by the re-weighting method at 300 K and 700 K, respectively.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036648&req=5

f2-2_1: (A) The trajectory of the potential energy of Loop R8 as determined by the FBMcMD method with the GBSA model. (B) Energy distribution of the multicanonical ensemble (solid line). The dotted curve and dashed curve represent the canonical ensembles calculated by the re-weighting method at 300 K and 700 K, respectively.
Mentions: The potential energy trajectory of a multicanonical simulation is shown in Fig. 2A for the 8-residue flexible loop system in RNase A designated as Loop R8 in Fig. 1. Loop R8 is composed of flexible loop residues 64 to 71, and 27 other surrounding residues. The potential energy was initially ca. −290 kcal/mol, and gradually increased to cover a wide energy range by random-walking in the energy space. Figure 2B shows the energy distribution of the multicanoni-cal ensemble for this flexible loop system obtained by the current FBMcMD method, with the energy distributions for the re-weighted canonical ensembles at 300 K and 700 K. The flat energy distribution in Fig. 2B indicates that the current method succeeded in generating the multicanonical ensemble.

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.