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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.

No MeSH data available.


Structure of RNase A: A pipe model of RNase A (PDB code, 2AAS)5 drawn using MOLMOL54. The diameter of the pipe for the RNase A backbone is proportional to the RMSDs of the backbone atoms, obtained from the 32 distance-geometry conformations. The green and blue pipes represent Loop R8 with 8 residues and Loop R12 with 12 residues, respectively.
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f1-2_1: Structure of RNase A: A pipe model of RNase A (PDB code, 2AAS)5 drawn using MOLMOL54. The diameter of the pipe for the RNase A backbone is proportional to the RMSDs of the backbone atoms, obtained from the 32 distance-geometry conformations. The green and blue pipes represent Loop R8 with 8 residues and Loop R12 with 12 residues, respectively.

Mentions: The elucidation of the relationship between the three-dimensional (3D) structure of a biological macromolecule and its function remains an essential theme in structural biological research. Flexible loops play an important role in molecular functions, including those pertaining to enzymatic activity, macromolecule-macromolecule binding and ligand recognition1–4. In many cases the flexible loops adopt particular rigid conformations when they function, such as in the case of ligand binding. However, in their ligand-free state, the structures are too flexible to be precisely and unambiguously identified due to the low electron densities derived from X-ray crystallography or the few Nuclear Overhauser Effect (NOE) cross peaks derived from NMR spectroscopy. In Fig. 1, two flexible loops of bovine ribonuclease A (RNase A) are shown with the 32-loop conformations observed by NMR (PDB code, 2AAS)5. Here, the diameter of the pipe model for the backbone of RNase A corresponds to the root-mean square deviations (RMSDs) of the backbone atoms, obtained from the 32 distance-geometry conformations.


Generation of a flexible loop structural ensemble and its application to induced-fit structural changes following ligand binding
Structure of RNase A: A pipe model of RNase A (PDB code, 2AAS)5 drawn using MOLMOL54. The diameter of the pipe for the RNase A backbone is proportional to the RMSDs of the backbone atoms, obtained from the 32 distance-geometry conformations. The green and blue pipes represent Loop R8 with 8 residues and Loop R12 with 12 residues, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

f1-2_1: Structure of RNase A: A pipe model of RNase A (PDB code, 2AAS)5 drawn using MOLMOL54. The diameter of the pipe for the RNase A backbone is proportional to the RMSDs of the backbone atoms, obtained from the 32 distance-geometry conformations. The green and blue pipes represent Loop R8 with 8 residues and Loop R12 with 12 residues, respectively.
Mentions: The elucidation of the relationship between the three-dimensional (3D) structure of a biological macromolecule and its function remains an essential theme in structural biological research. Flexible loops play an important role in molecular functions, including those pertaining to enzymatic activity, macromolecule-macromolecule binding and ligand recognition1–4. In many cases the flexible loops adopt particular rigid conformations when they function, such as in the case of ligand binding. However, in their ligand-free state, the structures are too flexible to be precisely and unambiguously identified due to the low electron densities derived from X-ray crystallography or the few Nuclear Overhauser Effect (NOE) cross peaks derived from NMR spectroscopy. In Fig. 1, two flexible loops of bovine ribonuclease A (RNase A) are shown with the 32-loop conformations observed by NMR (PDB code, 2AAS)5. Here, the diameter of the pipe model for the backbone of RNase A corresponds to the root-mean square deviations (RMSDs) of the backbone atoms, obtained from the 32 distance-geometry conformations.

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.