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Insights From Simulations Into The Mechanism Of Human Topoisomerase I: Explanation For A Seeming Controversy In Experiments
- Publication Year :
- 2013
- Publisher :
- Aperta, 2013.
-
Abstract
- Human topoisomerase-I is a vital enzyme involved in cellular regulation of DNA supercoiling. We extend our previous work on wild type enzyme [13] to study how different enzyme mutants with various parts of the protein clamped by disulfide mutations affect DNA rotation. Three different mutants have been simulated; they are clamped enzyme-DNA systems in which the disulfide bridge is formed by replacing His367 and Ala499, Gly365 and Ser534, and, respectively, Leu429 and Lys436 with Cys pairs. The first of these mutants, a 'distally clamped' enzyme, mimics the experimental study of Carey et al. [11], which reports DNA rotation within the clamped enzyme. The second one, a 'proximal clamp', mimics the study of Woo et al. [12], who do not observe DNA rotation. The third is a newly suggested mutant that clamps the hinge for protein opening; we use it to test a hypothesis on negative supercoil relaxation. Our simulations show that the helical domain alpha 5 totally melts in relaxation of positive supercoils when the enzyme is proximally clamped, while it preserves its structure very well within the distally clamped one. Moreover, a distally clamped protein permits DNA rotations in both directions, while the proximal clamp allows rotations only for negatively supercoiled DNA. These observations reconcile the two seemingly contradictory experimental findings, suggesting that subtle changes in the location of the disulfide bridge alter the mechanism significantly. (C) 2013 Elsevier Inc. All rights reserved.
- Subjects :
- Models, Molecular
Protein Conformation
Stereochemistry
Mutant
Hinge
Quantitative Structure-Activity Relationship
Molecular Dynamics Simulation
Biology
chemistry.chemical_compound
Molecular dynamics
Materials Chemistry
Humans
Physical and Theoretical Chemistry
Spectroscopy
chemistry.chemical_classification
Topoisomerase
Cellular Regulation
DNA
Computer Graphics and Computer-Aided Design
Molecular Docking Simulation
Enzyme
DNA Topoisomerases, Type I
chemistry
biology.protein
Biophysics
Nucleic Acid Conformation
DNA supercoil
Protein Binding
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....aeb5387b620be365aef449e2a8f9574d