Sulfur-substitution-induced base flipping in the DNA duplex

Area of Science:

• Molecular Biology
• Computational Chemistry
• Biophysics

Background:

• Base flipping is crucial for DNA accessibility and biological processes.
• Sulfur substitution of guanine to thioguanine affects DNA thermodynamic stability.
• Experimental data on thioguanine's effect on GC base pairs and GT mismatches show decreased GC base pair lifetime.

Purpose of the Study:

• To investigate thermodynamic profile variations in base flipping upon sulfur substitution using molecular simulations.
• To evaluate the accuracy of different AMBER force fields in predicting these thermodynamic changes.
• To computationally resolve conflicting experimental observations regarding the relative stability of S6G-C base pairs and S6G-T mismatches.

Main Methods:

• Equilibrium and nonequilibrium free energy simulations.
• Utilized three AMBER force fields (bsc0, bsc1, OL15) for nucleotide systems.
• Constructed free energy profiles along the base flipping pathway.

Main Results:

• AMBER force fields bsc1 and OL15 qualitatively and quantitatively predict sulfur-substitution dependent thermodynamic behavior.
• The bsc0 modification showed only qualitative agreement.
• Computational free energy profiles resolved conflicting experimental data on S6G-C vs. S6G-T stability.

Conclusions:

• Last-generation AMBER force fields (bsc1, OL15) are reliable for studying sulfur substitution effects on DNA thermodynamics.
• Computational methods can accurately predict base flipping thermodynamics and resolve experimental ambiguities.
• Sulfur substitution significantly alters DNA base pair stability and dynamics.