Structural Properties And Stability Of G-quadruplex Studied By Molecular Simulations

In guanine-rich nucleic acid sequences, whether in vivo or in vitro, the formation of several consecutive G-quartets can form inter-molecular or intra-molecular four-stranded structures, termed G-quadruplexes. G-quadruplex has been widely investi-gated because it has the potential of controlling the replication of DNA and the ex-pression of gene, when it stability exists in telomere and promoter. So, the stability of G-quadruplex is a basic and important issue for us to pay attention to. In order to understand the stability of G-quadruplex and found factors which affect it, we deployed lots of molecular simulations among G-quadruplexes. As a result, we found some new characters about the loop of G-quadruplex, gave explanations for some experimental results and contributed to the understanding of G-quadruplex structure.Loops which are linkers connecting G-strands and supporting the G-stem core in G-quadruplex are important for biological roles of G-quadruplexes. In chapter2, A se-ries of molecular dynamics (MD) simulations were carried out to investigate the struc-tural dynamics of TTA loops. We found that, the TA base pair formed in TTA loops are very stable, the occupied of all hydrogen bonds are more than0.95and the TA base pair makes the adjacent G-quartet more stable than others. For edgewise loop and diagonal loop, most loop bases are stacking with others, only few bases have considerable free-dom. The stability of these stacking structures is distinct. Part of the loops, especially TA base pairs, and base stacking with the G-quartet, maintain certain stable conforma-tions in the simulation, but other parts, like TT or TA stacking structure, are not stable enough. For the first time, spontaneous conformational switches of TTA edgewise loops were observed in our long time MD simulations.G-quadruplex is a specific DNA structure stabilized by cations dwelling between adjacent G-quartets. The cation which dwelling in the coordination sites can moving to the bulk solution through two terminals of G-quadruplex in an asymmetrical manner. In chapter3, we used molecular dynamics simulations and adaptive biasing force method to investigate the influence of glycosidic bond orientations of guanosines on the mov-ing of cations through the G-quartet. We found that syn glycosidic bond orientation penalizes the escaping of K+ions, which result in the asymmetrical cations movement through the two terminals of G-quadruplexes. Nonetheless, the syn orientations have slight influence on the energy barrier for Na+ions penetrating the terminal G-quartet for its relatively smaller radius.In chapter4, we studied the influence of loop to the ion-exchange of G-quadruplex. We found that most species of loop structure and loop base have influence on the escap- ing of cations, except the "pure" double chain reversal loop, which resides on the lateral side of G-stem. For edge wise loop and diagonal loop, which reside on the upper side and lower side of G-quadruplex, which is on the ion-exchange pathway, have influence on the cations in most of time:the loop base can stacking with G-quartet, which makes the G-quartet more stable and the ions escaping more difficult. But some times when no stacking exists, the loop have no influence on the escaping of cations. Besides, we found a special situation that when there are carbonyl O atoms on the pathway of ion-exchanges, as to the electrostatic interaction between cation and carbonyl O atoms, the escaping of cations becomes easier than others.In order to maintain the stable G-quadruplex structure, then inhibit the replication of DNA and the expression of gene, we need to design some small drug molecule to interact with G-quadruplex specifically. In chapter5, we investigated the interaction of two telomestain derivatives and htel in molecular level by using molecular dynamics simulations, we found that the binding of drug induced the disrupt of AT base pair be-tween loop bases on the upper side of htel. Then, after calculating the binding enthalpy, we found that even though the interaction of drug and htel is strong, but as to it disrupt the AT base pair and the stacking structure between AT and upper G-quartet, lead to the total enthalpy exchange is not as remarkable as we think. On the other hand, the dis-ruption of AT base pair induced the increase of conformational entropy of htel, which is bigger than the change of enthalpy, especially in the case of drug named HXDV. The results is in agreement with experiments.