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Conformational selection or induced fit for Brinker and DNA recognition
Authors:Qin Fang  Jiang Yaobin  Chen Yue  Wu Maoying  Yan Guanwen  Ye Wenjun  Li Yixue  Zhang Jian  Chen Hai-Feng
Institution:College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
Abstract:Brinker is the key target protein of the Drosophila Decapentaplegic morphogen signalling pathway. Brinker is widely expressed and can bind with DNA. NMR spectra suggest that apo-Brinker is intrinsically unstructured and undergoes a folding transition upon DNA-binding. However, the coupled mechanism of binding and folding is poorly understood. Here, we performed molecular dynamics (MD) simulations for both bound and apo-Brinker to study the mechanism. Room-temperature MD simulations suggest that Brinker becomes more rigid and stable upon DNA-binding. Kinetic analysis of high-temperature MD simulations shows that both bound and apo-Brinker unfold via a two-state process. The time scale of tertiary unfolding is significantly different between bound and apo-Brinker. The predicted Φ-values suggest that there are more residues with native-like transition state ensembles (TSEs) for bound Brinker than for apo-Brinker. The average RMSD differences between bound and apo-Brinker and Kolmogorov-Smirnov (KS) test analysis illustrate that Brinker folding upon DNA-binding might obey induced-fit mechanism based on MD simulations. These methods can be used for the research of other biomolecular folding upon ligand-binding.
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