Study On The Structure And Properties Of G-Quadruplex In Aqueous Solutions By ABEEM?? Polarized Force Field

The human telomere sequence G-quadruplex is a special DNA secondary structure that is widely present in cancer cells.Experiments have confirmed that a stable G-quadruplex can be used as an antitumor drug target.Therefore,the structure and properties of G-quadruplexes have became a hot topic in life science.In this thesis,the atom-bond electronegativity equalization fluctuating charge polarizable force field(ABEEM??PFF)is developed and applied to investigate the parallel structure of G-quadruplex(PDB code:1KF1)by Molecular Dynamics(MD)Simulation.First,the improper dihedral angle parameters of the G-quadruplex and the related ABEEM??PFF parameters of K~+were refitted and determined.Then,ABEEM??PFF was used to explore the parallel structure of G-quadruplex(1KF1)and its stability.Our results show:(1)In the K~+aqueous solution,four nearby guanine(G)bases can form a stable near-plane G-tetrad through eight Hoogsteen hydrogen bonds,and K~+can exist stably in the middle of two layers of G-tetrad.The three-layer stable G-tetrads get more stable through?-?stacking between G-tetrads.(2)In the Na~+aqueous solution,Na~+cannot stably locate in the middle of the two G-tetrads,resulting in a significant deformation of the planar G-tetrad structure.This is consistent with experimental report that the parallel G-quadruplexes are only present in aqueous K~+solution.Furthermore,the three G-tetrads in the 1KF1 are linked by four G-chains,while the pentose-phosphate backbone in the G-chain plays a supporting role,and the three linked double chain reversal loops(TTA loops)play a key role to preserve the parallel structure of G-quadruplex.It is also found that the TTA loops are more flexible during simulation,but the TA base pairs within them can maintain a certain stacking structure,and then prompt the relative stability of the TTA loops.It is also found that the exocyclic adenine(A)at the 5?end of the 1KF1 invertes until it stacks with a guanine in the nearest G-tetrad,and remaines this conformation during the simulation.In addition,the QM method and the ABEEM??PFF were used to calculate and analyze the charge distributions of the 1KF1 system during the simulation.The linear correlation confficients of the charge distributions from the two methods are nearly 0.95.