Structuring Disorder via Supervised Molecular Dynamics: Uncovering Arginine-Glycine-Glycine-Mediated Ribonucleic...

Area of Science:

• Molecular Biology
• Structural Biology
• Biophysics

Background:

• RNA plays a critical role in gene regulation and cellular homeostasis.
• RNA-binding proteins utilize intrinsically disordered regions (IDRs), particularly arginine-glycine-rich motifs, for versatile interactions.
• The dynamic nature of IDRs poses challenges for structural characterization and computational modeling of RNA-protein complexes.

Purpose of the Study:

• To explore the applicability of supervised molecular dynamics (SuMD) for reconstructing RNA-disordered protein recognition mechanisms at atomic resolution.
• To capture the multistep nature of RNA-protein binding processes involving IDRs.
• To generate structural hypotheses for RNA-IDR complexes and guide therapeutic design.

Main Methods:

• Utilized supervised molecular dynamics (SuMD) simulations.
• Focused on two experimentally resolved systems: SF3A1-UBL/U1-SL4 and FUS RRM/U1-SL3.
• Applied the approach to a prospective system lacking experimental structural data.

Main Results:

• SuMD successfully reproduced association pathways for both disordered and structured regions of RNA-binding proteins.
• The method captured transient contacts and interaction hierarchies in RNA-protein recognition.
• A model for a prospective system was generated, consistent with experimental mutagenesis data.

Conclusions:

• SuMD is a powerful tool for understanding RNA-IDR recognition mechanisms at atomic resolution.
• This approach provides valuable structural insights into dynamic RNA-protein interactions.
• The findings facilitate the rational design of therapeutics targeting RNA-protein interactions.