Journal
CCS CHEMISTRY
Volume 3, Issue 2, Pages 1026-1039Publisher
CHINESE CHEMICAL SOC
DOI: 10.31635/ccschem.020.202000202
Keywords
free-energy simulation; base flipping; TNA; AMBER force fields; salt concentration
Categories
Funding
- National Key R&D Program of China [2016YFA0501700]
- National Natural Science Foundation of China [21433004, 31700646, 21933010]
- NYU Global Seed Grant
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TNA, an analogue of DNA, exhibits higher chemical stability and less reactive groups, while maintaining the thermodynamic stability in the duplex. Simulation studies investigated the mutation-dependent behavior of TNA in base flipping, highlighting the importance of simulating experimental conditions with sufficient salt concentrations.
Threofuranosyl nucleic acid (TNA) is an analogue of DNA with a shift in the internucleotide linkages from the wild-type 5'-to-3' direction to 3'-to-2.' This alteration leads to higher chemical stability, less reactive groups, and lower conformational flexibility. Experimental observations indicate that these characteristic changes are attributable to a minimal perturbation of the interaction network, but the thermodynamic stability of the duplex remains unaltered in the TNA mutation. We applied the equilibrium and nonequilibrium free-energy simulations employing three popular assisted model building with energy refinement (AMBER) force fields for nucleotides to investigate this mutation-dependent behavior in the base flipping from T (DNA) residue to the T-to-TFT mutation (TNA) computationally. The force fields were performed similarly, as described in the base-paired state. However, after exploring the high-energy regions with free-energy simulations, we observed that these three force fields behaved differently. Previous reports conclude that the net-neutral and excess-salt simulations provided similar results. Nonetheless, our free-energy simulation indicated that the presence of excess salt affected the thermodynamic stability. The free-energy barrier along the base-flipping pathway was generally elevated upon the addition of excess salts, but the relative height of the free-energy barriers in DNA and TNA duplexes did not change significantly. This phenomenon emphasizes the importance of adding sufficient salts in the simulation scheme to reproduce the experimental condition.
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