A human transcription factor in search mode.

Area of Science:

• Molecular Biology
• Structural Biology
• Biophysics

Background:

• Transcription factors (TFs) undergo conformational changes to regulate DNA binding affinity.
• The mechanism of TF conformational switching from search to recognition modes is often unclear.
• High-resolution structures of non-specific TF-DNA complexes are rarely available.

Purpose of the Study:

• To investigate the conformational dynamics of human mitochondrial transcription termination factor 1 (MTERF1) during DNA binding.
• To characterize the non-specific DNA search mode of MTERF1.
• To provide insights into the MTERF1-DNA recognition mechanism.

Main Methods:

• Molecular dynamics (MD) simulations of apo MTERF1 to explore conformational flexibility.
• Docking of sampled MTERF1 conformations to B-DNA.
• Unrestrained MD simulations of MTERF1-B-DNA complexes to observe binding and diffusion.

Main Results:

• Simulations of apo MTERF1 revealed significant flexibility, sampling conformations suitable for B-DNA major groove binding.
• MTERF1-B-DNA complexes formed, allowing spontaneous diffusion of the protein on the DNA.
• The specific MTERF1-DNA complex involves significant DNA distortion, with MTERF1 adopting a conformation incompatible with B-DNA.

Conclusions:

• MTERF1-DNA binding and recognition are driven by the intrinsic dynamics of its superhelical topology.
• MTERF1 employs a conformational selection mechanism, utilizing its flexibility to search for and bind DNA.
• Understanding MTERF1's dynamic search mechanism provides a basis for its role in mitochondrial transcription termination.