Theoretical Simulation Of Synergistic Mechanism Between Halogen Bond And Hydrogen Bond

Halogen bond,as a important noncovalent interaction parallel to hydrogen bond in drug target interaction,has attracted more and more attention in the field of drug design in recent years.Different from hydrogen bond,the covalent halogen atoms can form halogen bond and hydrogen bond at the same time because of having both negative and positive charge region(?-hole).These two kinds of interactions can compete and cooperate with each other and regulate the interaction between drug and target.At the same time,water molecules exist around the binding pocket and form hydrogen bond with covalent halogen atoms.However,we still know little about how water molecules interact with covalent halogen atoms and how to exert the regulation mechanism on drug target interaction.Understanding this mechanism is of great importance for improving the effect of halogen drugs and designing new drugs.Taking the interaction of the important cancer-related protein(p53)and its stabilizer(phikan5196(p96))as an example,a hybrid quantum mechanical/molecular mechanics(QM/ MM)-molecular dynamics(MD)simulation method was used to explore the competitive synergetic mechanism of the halogen bond/hydrogen bond in the complex.We studyed the dynamic regulation mechanism of the three water molecules on the halogen bond.the main topics of this thesis are as follows: First,author had adopted the molecular dynamics simulation method to get the trajectories of the system.Then,by the analysis of the probability distribution and the correlation between halogen bond and hydrogen bond in the system,author studyed the important role of the three water on the halogen bond and the difference of the polarization effect on the I atom.Then,all the trajectories were clustered,the dynamic polarization effect of three water molecules on the halogen bond was studied.Finally,author calculated the charge transfer integral and interaction energy between P96 and the receptor,and illustrated the relationship between the halogen bond and the hydrogen bond from the view of QM.The main results are as follows:(1)The presence of three water molecules can enhance the halogen bond.(2)A water molecule shows a stronger polarization effect than the other two water molecules.(3)The hydrogen bonds formed by the three water molecules can enhance the halogen bond,but can‘t achieve the best polarization effect at the same time due to the steric effect.In general,this paper provides the effect of water molecules on the interaction of halogen bond and a new understanding of the relationship between hydrogen bond and halogen bond through molecular dynamic simulation.Moreover,the effect of water molecules on halogen bond can be used in the design of halogen-containing drugs.This dynamic polarization effect reveals the influence mechanism of water molecules on halogen bond in the dynamic simulation process,which is of great biological significance for the study of halogen bond/hydrogen bond interaction in other proteins.