Insights From Molecular Dynamics Simulations And Steered Molecular Dynamics Simulations To Exploit New Trends Of The Interaction Between HIF-1? And P300

Histone acetyltransferase p300 also known as p300 is an enzyme that,in humans,is encoded by the p300 gene.It functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling.This enzyme plays an essential role in regulating cell growth and division,prompting cells to mature and assume specialized functions(differentiate),and preventing the growth of cancerous tumors.The p300 protein appears to be critical for normal development before and after birth.Hypoxia-inducible factor-1(HIF-1),a member of the basic helix-loop-helix(b HLH)-PAS(period circadian protein,aryl hydrocarbon-receptor nuclear translocator,single-minded protein)family,is useful under hypoxic conditions.Under hypoxic conditions,HIF-1 binds to P300 and enters the nucleus to regulate gene transcription.Because of the ideal hypoxic environment in cancer cells,the interaction between HIF-1 and P300 is frequent,which makes the gene transcription and expression in cancer cells more active.Therefore,exploring the interaction between HIF-1 and P300 is of great biological significance for cancer treatment.Molecular dynamics simulation is a computer-based scientific research method derived from the kinetic equation of classical mechanics.It can provide the traditional experiment with the change of the periphery structure which it does not possess and the reliable mechanism theory research.When the theoretical calculation represented by molecular dynamics simulation is combined with traditional experiments,more scientific and rigorous results will be obtained.In this study,MD simulations were used to investigate the significant changes of secondary structure before and after HIF-1? binding and the dissociation of HIF-1? from p300.AMBER software was used to simulate the general dynamics of HIF-1?/p300 complex and P300 monomer,and to observe the changes of secondary structure and some macroscopic properties of HIF-1?/p300 complex.CAVER3.0 was used to predict the p300 channel,and NAMD software was used to simulate the tensile dynamics.The data of tensile dynamics simulation test were analyzed to explore the dissociation pathway of HIF-1? from p300.Results indicated that HIF-1?/p300 complex was stable during MD simulation.New H-bonds were made in the intra-chain of p300 with HIF-1? binding.Inhibiting the HIF-1?/p300 interaction modulated the HIF-1? identification of selective molecules,which may indicate the target metabolic and cellular processes that enable the survival and growth of tumors in cancer chemotherapy.CAVER 3.0 results suggested that three main tunnels were present,according to helices 1,2,and 3 ofp300.To explore the unbinding pathway for HIF-1? via p300,we selected helices 1,2,and 3 on the HIF-1? as a new ligand to explore the unbinding pathway via its own tunnel.For helix 1,R368 in p300 formed a H-bond with E816 in HIF-1?.A345 and D346 in p300 formed H-bonds with N803 in HIF-1?.A H-bond existed between K351(p300)and E789(HIF-1?).These molecules may be the key residues in the unbinding pathway via its tunnel.Our work provides a new idea for the study of the interaction between HIF-1a and p300,and provides a reference for finding the inhibitor sites of the interaction between HIF-1a and p300,thus providing some theoretical support for the treatment of cancer by inhibiting hypoxia-inducible factors.