Molecular Dynamics Study On The Interaction Mechanism Of Ligand And Targeting Protein

The study of the recognition and interaction of drugs and receptor proteins has been a hot topic and preface in the field of pharmacology and life sciences.The essence of the drug's efficacy is the result of interaction between ligands and the receptor macromolecule after the drugs reach their corresponding target.The binding of a drug with protein to form complex causes a change in the conformation of the receptor,which in turn triggers a series of physiological effects associated with the drug efficacy.Therefore,the study on the atomic-level interaction between drugs and targeting protein is of great significance in understanding the structure and function of proteins as well as the interaction mechanism between drugs and protein,which will provide theoretical guidance for the discovery of new targets and design of effective drug.The design provides theoretical guidance.The theoretical calculation of the binding free energy of the ligand to the targeting protein(protein tyrosine phosphatase 1B,fatty acid binding protein 4 and 5,epidermal growth factor receptor protein,heat shock protein)and the conformational changes caused by inhibitor bindings will provide a theoretical basis for the design of new drugs.Protein tyrosine phosphatase 1B(PTP1B)is one of the most promising target for designing and developing drugs to cure type-II diabetes and obesity.Molecular dynamics(MD)simulations combined with molecular mechanics generalized Born surface area(MM-GBSA)and solvated interaction energy(SIE)methods were applied to study binding differences of three inhibitors(ID: 901,941 and 968)to PTP1 B,the calculated results show that the inhibitor 901 has the strongest binding ability to PTP1 B among the current inhibitors.Principal component(PC)analysis was also carried out to investigate the conformational change of PTP1 B,and the results indicate that the associations of inhibitors with PTP1 B generate a significant effect on the motion of the WPD-loop.Free energy decomposition method was applied to study the contributions of individual residues to inhibitor bindings,it is found that three inhibitors can generate hydrogen bonding interactions and hydrophobic interactions with different residues of PTP1 B,which provide important forces for associations of inhibitors with PTP1 B.This research is expected to give a meaningfully theoretical guidance to design and develop of effective drugs curing type-II diabetes and obesity.Designing highly selective inhibitors of fatty acid binding proteins 4 and 5(FABP4 and FABP5)is of importance for treatment of some diseases related with inflammation,metabolism,and tumor growth.This study examined the binding selectivity of three inhibitors(5M7,65 X and 65Z)to FABP4/FABP5,the results suggest that all inhibitors associate more tightly with FABP4 than FABP5,and the main forces driving the selective bindings of inhibitors to FABP4 and FABP5 stem from the difference in the van der Waals interactions and polar interactions of inhibitors with two proteins.Meanwhile,a residue-based free energy decomposition method was applied to reveal molecular mechanism that inhibitors selectively interact with individual residues of two different proteins.The calculated results show that the binding difference of inhibitors to the residues(Phe16,Phe19),(Ala33,Gly36),(Phe57,Leu60),(Ala75,Ala78),(Arg126,Arg129)and(Tyr128,Tyr131)in(FABP4,FABP5)drive the selectivity of inhibitors toward FABP4 and FABP5.This study will provide great help for further design of effective drugs to protect against a series of metabolic diseases,arteriosclerosis,and inflammation.Epidermal growth factor receptor(EGFR)is one of the most promising targets for treatment of cancers,and double mutations T790M/L858 R lead to different degrees of drug resistance toward inhibitors.The results obtained from principal component analysis suggest that T790M/L858 R causes obvious disturbance on the structural stability of EGFR.Molecular mechanics-Poisson Boltzmann surface area(MM-PBSA)and residue-based free energy decomposition methods are integrated to explore drug-resistant mechanism of T790M/L858 R toward EGFR.The results show that the decrease in van der Waals interactions of inhibitors with the mutated EGFR relative to the wild-type(WT)one is the main force inducing drug resistance of T790M/L858 R toward inhibitors TAK-285,while drug resistance toward W2 P and HKI-272 is dominated by the decrease in van der Waals interactions and the increase in polar interactions.We expect that the information obtained from this study can aid rational design of effective drugs to relieve drug resistance of EGFR induced by T790M/L858 R.Heat shock protein 90(HSP90)is a promising target for treatment of cancer,and inhibitor bindings can lead to the degradation of its client proteins so as to generate combinatorial attack on tumor in multiple ways.In this work,140 ns molecular dynamics(MD)simulations were performed on six systems.Subsequent principal component analysis suggests that inhibitor bindings induce large conformational changes of HSP90,and these changes tend to enlarge the volume of the binding pocket to facilitate the entrance of inhibitors.Meanwhile,MM-PBSA,MM-GBSA and SIE methods were combined to predict binding free energies of inhibitors to HSP90.It is encouraging that the rank of the calculated results agrees well with that of the experimental ones.Per-residue energy and hierarchical clustering analyses indicate that residues in the group A are responsible for major contributions to inhibitor bindings.Individual contribution of each atom in residues to van der Waals interactions as well as analysis of hydrogen bonding interactions between inhibitors and HSP90 show that these two types of interactions of important residues with key regions of inhibitors are the main force for promoting binding of inhibitors to HSP90.We expect that this work can provide useful theoretical information for development of efficient inhibitors targeting HSP90.Up to now,MD simulation has become a universal tool to study conformation change of protein and ligand-protein binding mechanism.Principal component analysis(PCA)plays an important role in studying protein conformation.Moreover,several methods have been proposed to calculate binding free energies of inhibitors to proteins,such as free energy perturbation(FEP),thermodynamics integration(TI)and molecular mechanics Poisson-Boltzmann/generalized Born surface area(MM-PBSA/GBSA).Although the FEP and TI can obtain high accuracy in calculating binding free energies of inhibitor-protein complexes,they require a large amount of statistical sampling,which is expensive in computational time.On the contrary,MM-PBSA/GBSA methods can not only obtain rational results,but also save more computational resource and time.Moreover,these two methods have been successfully employed to predict binding free energies of inhibitors to proteins.We hope that the information acquired from this paper will be helpful to the design of inhibitors.