Topological frustration leading to backtracking in a coupled folding-binding process.

Area of Science:

• Protein Science
• Biophysics
• Molecular Biology

Background:

• Intrinsically disordered proteins (IDPs) lack stable structures, challenging the traditional sequence-structure-function paradigm.
• IDPs are crucial for biological processes, with their function encoded in amino acid sequences and conformational transitions upon binding.
• The colicin E3 (E3) and immunity protein Im3 complex is vital for bacterial survival, involving complex binding interactions.

Purpose of the Study:

• To investigate the binding mechanism of the intrinsically disordered protein E3 with its target Im3.
• To analyze the role of conformational transitions and potential frustrations in the E3/Im3 complex formation.
• To explore the influence of salt concentration on the binding pathway.

Main Methods:

• Coarse-grained molecular dynamics simulations were employed.
• Systematic free energy and transition path analyses were performed.
• Conformational analysis was conducted to understand binding intermediates.

Main Results:

• Backtracking of the E3 N-terminal segment was observed during binding, influenced by salt concentration.
• Initial N-terminal binding often misorients an E3 central hairpin, causing topological frustration.
• This frustration leads to the observed N-terminal backtracking, regulating the binding pathway.

Conclusions:

• The study provides mechanistic insights into the coupled folding-binding process of the E3/Im3 complex.
• Topological frustration is identified as a potential regulatory mechanism in IDP binding.
• These findings advance our understanding of how IDPs achieve function through dynamic conformational changes.