How Binding Site Flexibility Promotes RNA Scanning by TbRGG2 RRM: A Molecular Dynamics Simulation Study

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• RNA recognition motifs (RRMs) are crucial protein domains for binding single-stranded RNAs.
• Understanding RRM-RNA interactions is vital for deciphering gene regulation and cellular processes.

Purpose of the Study:

• To investigate the dynamic binding mechanisms of the TbRGG2 RRM protein with uridine-rich RNA sequences.
• To elucidate how RRMs achieve rapid RNA sequence transitions and selectivity using molecular dynamics simulations.

Main Methods:

• Atomistic molecular dynamics simulations using the OL3-Stafix AMBER force field.
• Analysis of protein-RNA binding dynamics, including multiple binding modes and spontaneous association.
• Comparison of binding behavior with uridine-rich versus cytidine-containing RNA sequences.

Main Results:

• TbRGG2 RRM exhibits a primary binding mode and two supplementary modes involving adjacent nucleotides.
• The protein facilitates rapid transitions along U-rich RNA sequences through dynamic binding states.
• Non-native cytidines in the RNA sequence lead to complex stalling and destabilization.
• The RRM demonstrates efficient diffusion and robust selectivity for U-rich sequences despite a single binding pocket.

Conclusions:

• Protein dynamics and transient binding states are critical for RNA-binding protein interface mechanisms.
• TbRGG2 RRM employs a dynamic strategy for rapid RNA processing and sequence selectivity.
• This dynamic binding approach may be a general strategy for many RNA-binding proteins.