title: Conformational elasticity can facilitate TALE-DNA recognition.
abstract: Sequence-programmable transcription activator-like effector (TALE) proteins have emerged as a highly efficient tool for genome engineering. Recent crystal structures depict a transition between an open unbound solenoid and more compact DNA-bound solenoid formed by the 34 amino acid repeats. How TALEs switch conformation between these two forms without substantial energetic compensation, and how the repeat-variable di-residues (RVDs) discriminate between the cognate base and other bases still remain unclear. Computational analysis on these two aspects of TALE-DNA interaction mechanism has been conducted in order to achieve a better understanding of the energetics. High elasticity was observed in the molecular dynamics simulations of DNA-free TALE structure that started from the bound conformation where it sampled a wide range of conformations including the experimentally determined apo and bound conformations. This elastic feature was also observed in the simulations starting from the apo form which suggests low free energy barrier between the two conformations and small compensation required upon binding. To analyze binding specificity, we performed free energy calculations of various combinations of RVDs and bases using Poisson-Boltzmann surface area (PBSA) and other approaches. The PBSA calculations indicated that the native RVD-base structures had lower binding free energy than mismatched structures for most of the RVDs examined. Our theoretical analyses provided new insight on the dynamics and energetics of TALE-DNA binding mechanism.
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; UC Davis Genome Center and Department of Biomedical Engineering, One Shields Avenue, Davis, California, USA. Electronic address: leihx@big.ac.cn.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Lei
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Jiya
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, California, USA.
authors.forename: Enoch P
authors.initials: EP
authors.lastname: Baldwin
authors.affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Segal
authors.affiliation: UC Davis Genome Center and Department of Biomedical Engineering, One Shields Avenue, Davis, California, USA. Electronic address: duan@ucdavis.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Duan
mesh_terms: D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004548:Elasticity; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D016012:Poisson Distribution; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015534:Trans-Activators; D004247:DNA
keywords: Bound; Elasticity; Specificity; TALE; Unbound