Insight into G-DNA structural polymorphism and folding from sequence and loop connectivity through free energy...

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• G-quadruplexes are crucial nucleic acid structures.
• Understanding sequence-structure relationships is key to G-quadruplex function.
• Existing knowledge on loop and G-tract influences is incomplete.

Purpose of the Study:

• Investigate how loop length, loop sequence, and G-tract length affect G-quadruplex folding and stability.
• Characterize folding topologies and stability using explicit solvent molecular dynamics (MD) simulations.
• Provide new insights into G-quadruplex folding mechanisms.

Main Methods:

• Explicit solvent molecular dynamics (MD) simulations.
• Free energy analysis.
• Investigated eight loop types and six loop sequences, including varying G-tract lengths.

Main Results:

• MD simulations and free energy analysis generally align with experimental observations.
• Identified instability in left propeller loops, expanding G-quadruplex folding rules.
• Proposed explanations for human telomere sequence structures in K+ solutions.
• Short loops are typically less stable than longer loops; very short loops may form parallel multimers.

Conclusions:

• MD simulations with current force fields can complement experimental data.
• Calculations help dissect the influence of loop/G-tract length and orientation on G-quadruplex structure.
• Findings advance the understanding of G-quadruplex folding and stability determinants.