Molecular Dynamics Study Of The Interaction Between Ligands And BRDs Proteins

Bromodomain and extraterial(BET)protein is a kind of bromodomain protein,which can selectively binds to acetylated lysine in the tail of histone.Through this combination,chromatin remodeling factors and transcription factors can move to the specific transcriptional sites of gene,thus regulating a series of important biological activities.Bromodomain-containing protein 4(BRD4)of BET protein involves in the regulation of cell cycle progression,cell apoptosis and cell differentiation in different tissues.It plays a crucial role in cell malignant transformation,tumorigenesis and progression.Inhibiting the activity of BRD4 protein can provide potential therapeutic effects for inflammation,a variety of cancer and other diseases.Therefore,BRD4 protein is a promising target for the treatment of cancer,and its corresponding inhibitors are widely used in the modification and design of anticancer drugs.In this paper,we studied the interaction mechanism of subfamily proteins of BET protein family with small molecular inhibitors.In Chapter 4th,molecular dynamics simulation and principal component analysis were used to study the effects of the inhibitors XD29(57G),XD35(57F)and XD28(57F)on the conformation of the first domain of BRD4 protein(BRD4-1).The results show that inhibitor bindings have significant effects on the movement of ZA-Loop in BRD4-1.In addition,in order to further study the binding abilities of these three inhibitors to BRD4-1,the binding free energy of inhibitors with BRD4-1 was calculated by using the molecular mechanics Poisson-Boltzmann surface area(MM-PBSA),and the calculation results indicate that the binding ability of L28 binding to BRD4-1 protein is the strongest.The analysis of energy decomposition and hydrogen bond shows that Pro82,Leu92,Asn140 and Ile146 play an important role in the binding process of BRD4-1 with the inhibitor.In chapter 5th,the binding selectivity of the inhibitors RVX297,BSP,JQ1,SF2523 and CPD2 to the two domains(BD1 and BD2)of BRD4 protein was studied.The results reveal that inhibitor bindings have different effects on the movement of ZA-Loop in BD1 and BD2.The calculations of alanine mutation and depressant residue interaction spectra show that thefive inhibitors have obvious differenence on binding selectivity to BD1 and BD2.Binding free energy calculation results indicate that the binding ability of RVX297,BSP and JQ1 to BD2 is stronger than that of BD1,but the binding ability of SF2523 to BD2 is obviously weaker than that of SF2523 to BD1.However,the selectivity of CPD2 to BD1 and BD2 is not much different.In Chapter 6th,the BRD9 and BRD4 subfamilies of the BRDs family have different physiological functions in different tissues.In this work,the selectivity mechanism of three inhibitors N1 D,TVU and 5V2 to BRD9 and BRD4 was studied.The results show that the three inhibitors bind more closely to BRD9 than to BRD4.The dissociation of free energy indicates that some important residues that located in BC-Loop and ZA-Loop,such as Phe44,Ile53,Asn100,Thr104 of BRD9 and Pro82,Lys91,Asn140,Asp144 of BRD4,which play an important role in the selectivity of the inhibitors to BRD9 and BRD4 through the interaction of electrostatic and van der Waals.On the one hand,the dynamic information of protein system with time can be obtained by molecular dynamics simulation;on the other hand,the thermodynamic information of protein system can also be obtained.We hope that the molecular dynamics studies in this paper will not only be helpful to further understand the internal kinetic changes of proteins caused by inhibitor binding,but also provide a theoretical basis for the design of highly selective anticancer drugs for proteins in the BRDs family.