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Local conformational changes in the DNA interfaces of proteins.

ABSTRACT: When a protein binds to DNA, a conformational change is often induced so that the protein will fit into the DNA structure. Therefore, quantitative analyses were conducted to understand the conformational changes in proteins. The results showed that conformational changes in DNA interfaces are more frequent than in non-interfaces, and DNA interfaces have more conformational variations in the DNA-free form. As expected, the former indicates that interaction with DNA has some influence on protein structure. The latter suggests that the intrinsic conformational flexibility of DNA interfaces is important for adjusting their conformation for DNA. The amino acid propensities of the conformationally changed regions in DNA interfaces indicate that hydrophilic residues are preferred over the amino acids that appear in the conformationally unchanged regions. This trend is true for disordered regions, suggesting again that intrinsic flexibility is of importance not only for DNA binding but also for interactions with other molecules. These results demonstrate that fragments destined to be DNA interfaces have an intrinsic flexibility and are composed of amino acids with the capability of binding to DNA. This information suggests that the prediction of DNA binding sites may be improved by the integration of amino acid preference for DNA and one for disordered regions.

SUBMITTER: Sunami T

PROVIDER: S-EPMC3571985 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Local conformational changes in the DNA interfaces of proteins.

Sunami Tomoko T Kono Hidetoshi H

PloS one 20130213 2

When a protein binds to DNA, a conformational change is often induced so that the protein will fit into the DNA structure. Therefore, quantitative analyses were conducted to understand the conformational changes in proteins. The results showed that conformational changes in DNA interfaces are more frequent than in non-interfaces, and DNA interfaces have more conformational variations in the DNA-free form. As expected, the former indicates that interaction with DNA has some influence on protein s ...[more]

PMID: 23418514

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Project description:Protein conformational changes and dynamic behavior are fundamental for such processes as catalysis, regulation, and substrate recognition. Although protein dynamics have been successfully explored in computer simulation, there is an intermediate-scale of motions that has proven difficult to simulate - the motion of individual segments or domains that move independently of the body the protein. Here, we introduce a molecular-dynamics perturbation method, the Rotamerically Induced Perturbation (RIP), which can generate large, coherent motions of structural elements in picoseconds by applying large torsional perturbations to individual sidechains. Despite the large-scale motions, secondary structure elements remain intact without the need for applying backbone positional restraints. Owing to its computational efficiency, RIP can be applied to every residue in a protein, producing a global map of deformability. This map is remarkably sparse, with the dominant sites of deformation generally found on the protein surface. The global map can be used to identify loops and helices that are less tightly bound to the protein and thus are likely sites of dynamic modulation that may have important functional consequences. Additionally, they identify individual residues that have the potential to drive large-scale coherent conformational change. Applying RIP to two well-studied proteins, Dihdydrofolate Reductase and Triosephosphate Isomerase, which possess functionally-relevant mobile loops that fluctuate on the microsecond/millisecond timescale, the RIP deformation map identifies and recapitulates the flexibility of these elements. In contrast, the RIP deformation map of alpha-lytic protease, a kinetically stable protein, results in a map with no significant deformations. In the N-terminal domain of HSP90, the RIP deformation map clearly identifies the ligand-binding lid as a highly flexible region capable of large conformational changes. In the Estrogen Receptor ligand-binding domain, the RIP deformation map is quite sparse except for one large conformational change involving Helix-12, which is the structural element that allosterically links ligand binding to receptor activation. RIP analysis has the potential to discover sites of functional conformational changes and the linchpin residues critical in determining these conformational states.

Dataset Information

Local conformational changes in the DNA interfaces of proteins.

Publications

Local conformational changes in the DNA interfaces of proteins.

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