Thermodynamic Insights of Base Flipping in TNA Duplex: Force Fields, Salt Concentrations, and Free-Energy Simulation Methods  

作　　者：Zhaoxi Sun John Z.H.Zhang 

机构地区：[1]State Key Laboratory of Precision Spectroscopy,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200062 [2]NYU-ECNU Center for Computational Chemistry at NYU Shanghai,Shanghai 200062 [3]Department of Chemistry,New York University,NY,NY 10003

出　　处：《CCS Chemistry》2021年第2期1026-1039,共14页中国化学会会刊（英文）

基　　金：supported financially by the National Key R&D Program of China(grant no.2016YFA0501700);National Natural Science Foundation of China(grant nos.21433004,31700646,and 21933010),and NYU Global Seed Grant.

摘　　要：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.

关 键 词：free-energy simulation base flipping TNA AMBER force fields salt concentration 

分 类 号：O64[理学—物理化学]