Study On The Mechanism Of Protein-ligand Selective Binding And Polarizable Force Field

After the development of MD simulation,the study of protein-ligand interactions such as recognition and binding has become a common phenomenon in computational biophysics.Molecular dynamic simulations can be in a certain time scale and atomic level dynamic display function details between protein and ligand,quantitative analysis of the hydrogen bonds,van der Waals effects,electrostatic interactions,hydrophobic,more can be achieved by quantum mechanics calculation,this in understanding the disease mechanism design and optimization,virtual screening,compound direction has played an increasingly important role.In the process of designing ligands for target proteins,attention is paid not only to their binding ability,but also to the specificity of ligand binding.PI4K?? and PI4K?? are two homologous proteins.The three-dimensional structure of PI4K?? and PI4K?? are very similar,but the distribution and function are not the same,and the two proteases are related to different human diseases respectively.This requires that ligands not only be designed to specifically bind to the PI4 K?s enzyme,but also to selectively bind to one of the proteins in PI4K?? or PI4K??.Molecular dynamic simulations provides a way to explain the selective binding of different ligands to PI4 K?s.Electrostatic interactions play an important role in protein-ligand interactions.Proteins and ligands are not only in a polarized solvent environment,but also have many charged and polarized side chains.It is necessary to deal with the polarization effect of electrostatic interaction correctly.The polarized charge force field PPC developed by our group contains electrostatic polarization effect,which can accurately simulate the electrostatic interaction between protein ligands.For metalloprotein systems,although many polarization force fields of zinc-containing proteins have been developed so far,the accuracy of these fields in zinc-containing protein and ligand systems has rarely been tested.In this paper,the mechanism of selective binding of two target proteins by different compounds was studied by means of molecular dynamics simulation and free energy calculation.Then,the PPC force field was used to simulate the protein and peptide system,and alanine scanning was conducted by MM-GBSA_IE method.Finally,a variety of force fields were tested for zinc-containing proteins and ligands,and a quantum-corrected polarization charge transfer force field was developed for zinccontaining proteins and ligands.In the second chapter,the interactions between seven compounds and homologous proteins PI4K?? and PI4K?? were analyzed by means of molecular dynamics simulation,binding free energy calculation and free energy decomposition of specific residues.The results showed that the two protein binding pockets were connected to a small pocket,and the two small pockets were of different sizes.Moreover,the pocket width of PI4K?? at residue I1840 was different from that of PI4K?? at residue V598.At the same time,although the skeletons of different compounds were similar,the side chain groups growing on the skeletons were different,which enabled compound 1 to bind the two proteins well,compound 2,3,4 selectively bound to PI4 K? protein,and compound 5,6,7 selectively bound to PI4 K? enzyme.In chapter 3,the interactions between the BIR3 and BIR2 domains of XIAP proteins and SMAC peptides were quantitatively studied by means of molecular dynamics simulation and MM-GBSA_IE alanine scanning.It is found that electrostatic polarization plays an important role in stabilizing the structure of protein-peptide complex in dynamic simulation.Moreover,compared with the standard(non-polarized)AMBER force field,the combination free energy calculated by using the PPC force field parameters and corresponding trajectories is in good agreement with the experimental value.Especially in the BIR3/SMAC system,the binding free energy obtained by alanine scanning has a good linear correlation with the mutation experimental data.In chapter 4,AMBER FF14 SB force field,cationic dummy atom model and nonbonding 12-6-4 force field were first tested against 76 zinc-containing protein and ligand systems.The results showed that AMBER's non-polarized field could not stabilize the coordination configuration of zinc ions with surrounding atoms in all the systems.For the systems with sulfonamide groups in ligands,the simulated results of the cationic dummy atom model and 12-6-4 force field were inconsistent with the crystal configuration.For the ligand system with the hydroxamic acid group,the cationic dummy atom model could not maintain the five-coordination configuration correctly,but the 12-6-4 bonding force field could correctly reflect the fivecoordination configuration of protein residues,groups and zinc ions.Then,the linear correlation between the binding free energy calculated by MM/PB(GB)method and the experimental value is compared.The results show that the test force field does not describe the interaction between zinc-containing proteins and ligands well,and there is still room for improvement.Therefore,I went on to develop a polarized charge transfer method(QPCT)for quantum correction of ligands.The method involves the effects of polarization and charge transfer through the calculation of quantum chemistry.By the same simulation test,the sulfonamide group system and the hydroxamic acid group system can respectively maintain the four and five coordination configurations consistent with the crystal configurations.