Exploring Metastable States along UUCG Unfolding Pathway Using Drude Force Field.

Area of Science:

• Molecular Biology
• Computational Chemistry
• Biophysics

Background:

• Hairpin loops in RNA are crucial for biological processes like folding and mRNA stability.
• UUCG hairpins are common and understanding their unfolding is key to RNA tertiary structure.
• Metastable states in RNA folding are important for diverse cellular functions.

Purpose of the Study:

• To investigate the metastable states of UUCG hairpin unfolding pathways.
• To compare the conformational sampling of nonpolarizable and polarizable force fields.
• To elucidate the role of distinct conformational states in UUCG hairpin function.

Main Methods:

• A hybrid approach combining Markov State Models (MSM) and molecular dynamics simulations.
• Analysis of 100 μs trajectories using the nonpolarizable CHARMM36 force field for initial partitioning.
• Further characterization of identified metastable states using the polarizable Drude force field.

Main Results:

• UUCG hairpin unfolding follows a parallel pathway model with microsecond time scales.
• Four distinct metastable states were identified, sampling different conformational spaces.
• The polarizable Drude force field revealed enhanced noncanonical hydrogen bonds and specific conformations (BI, syn, non-C3'-endo).

Conclusions:

• The nonpolarizable CHARMM36 force field provides an incomplete view of UUCG hairpin metastable states.
• The polarizable Drude force field offers a more accurate description of conformational properties.
• Understanding these states is vital for explaining the biological roles of non-native UUCG hairpin structures.