Conformational elasticity can facilitate TALE-DNA recognition

Hongxing Lei, Jiya Sun, Enoch P. Baldwin, David Segal, Yong Duan

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)315-346
Number of pages32
JournalAdvances in Protein Chemistry and Structural Biology
Volume94
DOIs
StatePublished - 2014

Fingerprint

Elasticity
Transcription
Conformations
DNA
Free energy
Solenoids
Molecular Dynamics Simulation
Energy barriers
Genome
Molecular dynamics
Amino Acids
Genes
Crystal structure
Switches
Transcription Activator-Like Effectors
Computer simulation
Proteins
Compensation and Redress

Keywords

  • Bound
  • Elasticity
  • Specificity
  • TALE
  • Unbound

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology

Cite this

Conformational elasticity can facilitate TALE-DNA recognition. / Lei, Hongxing; Sun, Jiya; Baldwin, Enoch P.; Segal, David; Duan, Yong.

In: Advances in Protein Chemistry and Structural Biology, Vol. 94, 2014, p. 315-346.

Research output: Contribution to journalArticle

Lei, Hongxing ; Sun, Jiya ; Baldwin, Enoch P. ; Segal, David ; Duan, Yong. / Conformational elasticity can facilitate TALE-DNA recognition. In: Advances in Protein Chemistry and Structural Biology. 2014 ; Vol. 94. pp. 315-346.
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