Specific recognition between YTHDF3 and m⁶ A-modified RNA: An all-atom molecular dynamics simulation study

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• YTHDF3 protein recognizes N6-methyladenosine (m6A) RNA modifications.
• The dynamic mechanism of m6A recognition and the role of its aromatic cage are not fully understood.

Purpose of the Study:

• To investigate the dynamic recognition mechanism of m6A-modified RNA by YTHDF3.
• To elucidate the role of aromatic cage residues in selective binding.
• To explore YTHDF3's selectivity towards unmethylated RNA.

Main Methods:

• Molecular dynamics (MD) simulations were employed.
• Comparative analyses of hydrogen bonds and binding free energy were performed.

Main Results:

• Conformational selectivity and induced-fit observed in YTHDF3-m6A RNA binding.
• Recognition loop and loop6 are critical for specific m6A recognition.
• m6A modification enhances YTHDF3-RNA complex stability via aromatic cage interactions and hydrophobicity.
• YTHDF3 preferentially recognizes m6A-modified RNA over unmethylated RNA.

Conclusions:

• The study clarifies the dynamic mechanism of YTHDF3's specific recognition of m6A-modified RNA.
• Identified key residues and interactions provide insights for structure-based drug design targeting RNA modifications.