Mechanical Stability and Unfolding Pathways of Parallel Tetrameric G-Quadruplexes Probed by Pulling Simulations

Area of Science:

• Biophysics
• Computational Biology
• Structural Biology

Background:

• Guanine quadruplexes (GQs) are noncanonical nucleic acid structures with crucial biological roles.
• GQ folding mechanisms and mechanical properties are not fully understood.
• Pulling experiments offer insights into GQ folding landscapes.

Purpose of the Study:

• To computationally explore the unfolding pathways and mechanical stability of tetrameric parallel GQs.
• To investigate the role of pulling force orientation on GQ structural transitions.
• To identify key unfolding events and intermediate conformations.

Main Methods:

• Steered molecular dynamics (SMD) simulations.
• Standard molecular dynamics (MD) simulations.
• Analysis of structural parameters and force components.

Main Results:

• Identified anisotropic mechanical properties of GQ conformational changes and unfolding.
• Demonstrated that the vertical component of pulling force significantly disrupts GQ structure and stability.
• Observed base unzipping as the dominant initial unfolding event, typically starting at the 3'-end.

Conclusions:

• Vertical pulling force magnitude is dependent on anchor positions and the number of G-quartets.
• Partial spiral conformations are transient intermediates during GQ (un)folding.
• Findings provide crucial insights into GQ mechanical behavior and folding dynamics.