Efficient in silico exploration of RNA interhelical conformations using Euler angles and WExplore

Area of Science:

• Structural biology
• Computational chemistry
• Virology

Background:

• HIV-1 TAR RNA is a critical motif for viral replication and a significant drug target.
• Its structural flexibility, characterized by large-amplitude helix reorientations, poses challenges for drug design.
• Previous computational studies struggled to adequately sample the diverse conformational landscape of TAR RNA.

Purpose of the Study:

• To achieve unprecedented sampling of the HIV-1 TAR RNA conformational ensemble.
• To identify key conformational switches enabling exploration of diverse structures.
• To provide a basis for future drug development efforts targeting HIV-1.

Main Methods:

• Utilized the WExplore algorithm combined with Euler angles for enhanced conformational sampling.
• Performed configuration space network analysis to understand interhelical dynamics.
• Employed a sample-and-select approach to identify novel drug target conformations.

Main Results:

• Generated a TAR RNA conformational ensemble with high agreement to experimental NMR data at reduced computational cost.
• Identified the intermittent A22-U40 base pair formation as a reversible switch controlling interhelical conformations.
• Located previously determined ligand-bound structures within the newly generated conformational network.

Conclusions:

• WExplore algorithm combined with order parameters offers an efficient method for exploring RNA conformational space.
• The A22-U40 base pair switch is a key mechanism governing TAR RNA flexibility.
• Novel TAR RNA conformations identified can guide future HIV-1 drug development.