Calculation Of Binding Free Energy And Research Of Binding Mechanism In Biomolecules

The interaction between biological molecules is a widespread phenomenon in nature and plays a crucial role in many life processes.Studying the interaction mechanism between biomolecules through theoretical calculation methods is an important approach for drug discovery,design and development.In this paper,molecular dynamics simulation(MD)and free energy calculation methods are combined to conduct an in-depth study of biological molecular systems,with the aim of revealing the binding mechanism between biological molecules that play important functions in life processes.The focus of the research is mainly on the following three aspects:(1)The first part of this paper investigates the interaction mechanism between Gquadruplex and berberine and its two derivatives from Chinese herbal medicine through molecular dynamics simulation.Compared to normal cells,telomerase shows significant activity in cancer cells.G-quadruplexes can inhibit the activity of telomerase and terminate the maintenance of telomeres,making them become potential targets for cancer therapy.Accurately simulating the interaction between G-quadruplexes and ligands is difficult due to the strong negative charge of G-quadruplex(nucleic acids).Therefore,various force fields(OL15 and BSC1)and charge models(AM1-BCC and RESP)are employed to test the interaction between G-quadruplex and ligand.The results show that the OL15+RESP combination obtains the most stable structure.Through B-factor analysis,charge calculation and hydrogen bond analysis,it is found that the ligand can stabilize the structure of G-quadruplex.By the calculation of energy under the MM/GBSA and IE,as well as structural analysis,this study find that compared with berberine,berberine derivatives can generate stronger van der Waals interactions with G-quadruplexe due to their special structural properties.These findings provide important theoretical guidance for designing new inhibitors targeting G-quadruplexes.(2)The second part of this paper explores the interaction mechanism between chaperone Hfq and OxyS sRNA,which is expressed as a transcriptional regulatory factor under oxidative stress conditions.Experimental studies find the N48 A mutation in the Hfq protein can enhance the binding affinity between the protein and OxyS sRNA,but also lead to defects in gene regulation.However,the interaction mechanism between Hfq protein and OxyS sRNA and the mechanism by which the N48 A mutation enhances affinity remain unclear.Therefore,in this work,molecular dynamics simulation is performed on Hfq and OxyS sRNA,and the relative binding free energy of Hfq wild type and N48 A mutant to OxyS sRNA is calculated by the combination of MM/GBSA and IE as well as FEP method.The calculated results have a good correlation with the experimental results.Energy calculations and residue decomposition show that the enhancement of binding affinity by the N48 A mutation is mainly due to the conformation change of the surrounding amino acids caused by the mutated residue,which strengthens the interaction between the surrounding residues and RNA.This part of the work provides important insights into the mechanism of gene expression regulation caused by protein mutations.(3)In the third part of this paper,the binding mechanism of tumor suppressor protein p53 and the peptide inhibitor pDIQ with the oncoprotein MDMX/MDM2 is studied by the non-polarized AMBER force field and the polarized PPC force field.Inhibiting the interaction between p53 and MDMX/MDM2 has become an effective approach for developing anti-tumor drugs.The study finds that the calculated binding free energy trend obtained by PPC polarizable force field is more consistent with experimental trend compared to non-polarized force field.Energy decomposition and structural analysis show that van der Waals interactions are the main driving force for the binding of p53/pDIQ to MDMX and the binding of p53/pDIQ to MDM2,and are the main reason for the weaker binding affinity of p53/pDIQ with MDMX compared to MDM2.This work provides theoretical guidance for studying the mechanism of protein-protein binding and designing dual inhibitors for p53-MDMX/MDM2.This paper uses molecular dynamics simulations to investigate the interaction mechanisms of biomolecules at the atomic level.This work provides guidance for the development of more effective anticancer drugs,and also provides new ideas and methods for the study of biomolecular interactions.