Replacing thymine with a strongly pairing fifth Base: A combined quantum mechanics and molecular dynamics study

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• The non-natural ethynylmethylpyridone C-nucleoside (W) is a thymidine (T) analog.
• W can be incorporated into oligonucleotides via automated synthesis.
• W forms a high-fidelity base pair with adenosine (A) and is accommodated in B-DNA.

Purpose of the Study:

• To computationally investigate the structural, stability, and dynamic effects of the W nucleoside in DNA.
• To complement experimental findings on W's properties.
• To rationalize W's impact on DNA duplexes.

Main Methods:

• Quantum mechanics (QM) calculations.
• Molecular dynamics (MD) simulations.

Main Results:

• QM calculations confirm increased A:W base pair stability over A:T due to CH-π interactions.
• W:G mispairing distorts base pair planarity, destabilizing DNA duplexes.
• MD simulations show minor geometric changes but groove alterations in DNA with A:W pairs.
• QM analysis reveals increased stacking energy for W compared to T.

Conclusions:

• The W nucleoside enhances DNA duplex stability and offers potential for biotechnological applications.
• Computational methods provide insights into the structural and energetic consequences of incorporating W into DNA.
• W's specific interactions explain its high fidelity with A and destabilization with G.