Study On Solvation Contribution Of Cation-π And Molecular Mechanism Of Interaction Between PYLs And PP2C

Cation-π interactions are widely found in protein-protein,protein-ligand,and protein-DNA interactions.Cation-π is an important noncovalent interaction and used in drug molecule design.Based on π system or cation provided by ligand,this interaction can be divided into cation-π or π-cation.Protein binding sites are predominantly hydrophobic compared to the rest of protein surfaces,and ligand providing π systems or cation can affect the hydrophobicity or hydrophilicity of ligand.The different hydrophobicity of ligands will cause difference in solvation contribution and affect the binding ability.Distinguishing the difference in solvation contribution of cation-π andπ-cation is important for drug molecular design.In this thesis,by screening the protein-ligand complex structure in the PDB database,2980 complexs with cation-πinteractions and 1780 complexes with π-cation interactions were obtained.By calculating and analyzing solvation energy,it was first discovered that the system with cation-π has less solvation contribution than π-cation system and is more beneficial to protein-ligand binding.Therefore,cation-π interaction can be considered for adoption in drug molecular design and guides the drug molecular design.Abscisic acid(ABA)plays an important role in improving plant stress resistance.ABA analogs regulate PYL receptors and randomly effect on the downstream protein PP2C.ABA analog is called agonist when binding with PYLs,which inhibits PP2C,exerting influence on drought resistance and the inhibition of seed germination.ABA analog is called antagonist when binding with PYLs without inhibiting PP2C.For example,the ABA analog pyrabactin is found to inhibit PP2C after binding to PYR1,but cannot inhibit PP2C after binding to PYL2.It is unclear that the molecular mechanism of ABA analogs regulating the interaction of PYLs with downstream proteins PP2C.In this thesis,the interactions of protein-protein were simulated by molecular dynamics simulation method.We got nine dynamic trajectories of ABA and its analogs.Hydrogen bond between PYLs-PP2C were monitored and the contributions of amino acid residues at the interface to binding energy were analyzed.We found that the hydrogen bonding and hydrophobic interactions of PYLs inhibiting PP2C interface are conserved and we explained the molecular mechanism between PYLs and PP2C interaction.Finally,combined with the conclusions of the above two parts,we applied the new strategy of drug molecular design on the virtual screening of ABA.On the one hand,the cation-π interaction was applied to the ABA system.On the other hand,we calculated protein-ligand binding energy and protein-protein binding energy to screen compounds.New compounds were obtained and the binding modes were determined.