Exploring potentially alternative non-canonical DNA duplex structures through simulation.

Area of Science:

• Structural Biology
• Computational Chemistry
• Molecular Modeling

Background:

• The Watson-Crick (WC) family represents the canonical right-handed double-stranded DNA (dsDNA) structure.
• Hopkins proposed an alternative, chirally distinct family of dsDNA models, termed configuration II.
• Configuration II dsDNA models include both right-handed (II-R) and left-handed (II-L) forms, with Z-DNA being an example of II-L.

Purpose of the Study:

• To estimate and compare the relative interstrand binding energies of different dsDNA models.
• To assess the stereochemical soundness of configuration II dsDNA forms using computational methods.
• To evaluate the performance of different AMBER force fields in simulating these dsDNA models.

Main Methods:

• Molecular dynamics (MD) simulations were performed on six DNA duplex models.
• MM-PBSA analysis was used to estimate relative interstrand binding energies.
• Three different AMBER force fields (bsc0, BSC [bsc1], and Olomouc 2015 [OL15]) were employed.

Main Results:

• Simulations support the stereochemical validity of configuration II dsDNA models.
• Recent force fields (BSC and OL15) successfully generated stable left-handed II-L structures.
• The bsc0 force field generated stable right-handed II-R structures, with a significant energy difference (~30 kcal/mol) between II-R and II-L.

Conclusions:

• Configuration II represents a viable alternative family of dsDNA structures.
• The choice of force field significantly impacts the stability of different dsDNA configurations.
• Advanced force fields are capable of accurately modeling less common dsDNA structures like II-L.