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Insights into conformational changes in AlkD bound to DNA with a yatakemycin adduct from computational simulations.

ABSTRACT: Structural integrity of DNA molecules is necessary for their information storage function. Cells rely on a number of pathways to ensure that the damage to DNA induced by endogenous and exogenous reagents is repaired. AlkD, a base excision enzyme, removes a damaged nucleobase by cleaving a glycosidic bond. Unlike many other base excision enzymes, AlkD does not flip a damaged nucleobase into a designated reaction pocket, and as such can repair nucleobases with larger adducts, such as yatakemycin. In this study, the structure and dynamics of AlkD have been investigated by classical molecular dynamics simulations. Several systems including apo-AlkD, and AlkD in complex with DNA, both with and without the yatakemycin adduct have been simulated. Comparison of the results for the apo-AlkD with AlkD with substrate (damaged or undamaged) indicates a high degree of motion of helix ?B in apo-AlkD, whereas this helix is observed to form various contacts when the substrate is bound. The calculated results are consistent with previous experimental studies that have suggested various residues involved in damage recognition, DNA binding, and base excision catalysis.

SUBMITTER: Silvestrov P

PROVIDER: S-EPMC6071674 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Insights into conformational changes in AlkD bound to DNA with a yatakemycin adduct from computational simulations.

Silvestrov Pavel P Cisneros G Andrés GA

Theoretical chemistry accounts 20180512

Structural integrity of DNA molecules is necessary for their information storage function. Cells rely on a number of pathways to ensure that the damage to DNA induced by endogenous and exogenous reagents is repaired. AlkD, a base excision enzyme, removes a damaged nucleobase by cleaving a glycosidic bond. Unlike many other base excision enzymes, AlkD does not flip a damaged nucleobase into a designated reaction pocket, and as such can repair nucleobases with larger adducts, such as yatakemycin. ...[more]

PMID: 30078993

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Project description:BACKGROUND: With increasing numbers of crystal structures of proteinratioDNA and proteinratioproteinratioDNA complexes publically available, it is now possible to extract sufficient structural, physical-chemical and thermodynamic parameters to make general observations and predictions about their interactions. In particular, the properties of macromolecular assemblies of multiple proteins bound to DNA have not previously been investigated in detail. METHODOLOGY/PRINCIPAL FINDINGS: We have performed computational structural analyses on macromolecular assemblies of multiple proteins bound to DNA using a variety of different computational tools: PISA; PROMOTIF; X3DNA; ReadOut; DDNA and DCOMPLEX. Additionally, we have developed and employed an algorithm for approximate collision detection and overlapping volume estimation of two macromolecules. An implementation of this algorithm is available at http://promoterplot.fmi.ch/Collision1/. The results obtained are compared with structural, physical-chemical and thermodynamic parameters from proteinratioprotein and single proteinratioDNA complexes. Many of interface properties of multiple proteinratioDNA complexes were found to be very similar to those observed in binary proteinratioDNA and proteinratioprotein complexes. However, the conformational change of the DNA upon protein binding is significantly higher when multiple proteins bind to it than is observed when single proteins bind. The water mediated contacts are less important (found in less quantity) between the interfaces of components in ternary (proteinratioproteinratioDNA) complexes than in those of binary complexes (proteinratioprotein and proteinratioDNA).The thermodynamic stability of ternary complexes is also higher than in the binary interactions. Greater specificity and affinity of multiple proteins binding to DNA in comparison with binary protein-DNA interactions were observed. However, protein-protein binding affinities are stronger in complexes without the presence of DNA. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the interface properties: interface area; number of interface residues/atoms and hydrogen bonds; and the distribution of interface residues, hydrogen bonds, van der Walls contacts and secondary structure motifs are independent of whether or not a protein is in a binary or ternary complex with DNA. However, changes in the shape of the DNA reduce the off-rate of the proteins which greatly enhances the stability and specificity of ternary complexes compared to binary ones.

Dataset Information

Insights into conformational changes in AlkD bound to DNA with a yatakemycin adduct from computational simulations.

Publications

Insights into conformational changes in AlkD bound to DNA with a yatakemycin adduct from computational simulations.

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