Insights from molecular dynamics simulations and steered molecular dynamics simulations to exploit new trends of the interaction between HIF-1α and p300

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in the expression of genes, whose function is exerted through protein–protein interactions (PPIs), such as the transcriptional co-activator (CREB)-binding protein (CBP) and p300. Under hypoxic conditions, HIF-1is stabilized and translocated to CBP or p300, leading to the hypoxic response cascade. Furthermore, the PPI between HIF and p300/CBP is a potential cancer target for their role in the hypoxic response. In this study, molecular dynamics (MD) simulation was used to explore the conformational change for the p300 binding to one subunit of HIF-1, namely HIF-1α. Results indicated that HIF-1α–p300 complex was stable during MD simulation. New H-bonds were made in the intra-chain of p300 with HIF-1α binding. Inhibiting the HIF-1α–p300 interaction modulated the HIF-1α 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 of p300. To explore the unbinding pathway for HIF-1α via p300, we selected helices 1, 2 and 3 on the HIF-1α 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 HIF1-α. A345 and D346 in p300 formed H-bonds with N803 in HIF-1α. A H-bond existed between K351(p300) and E789 (Hif1-α). These molecules may be the key residues in the unbinding pathway via its tunnel.

Communicated by Ramaswamy H. Sarma

Keywords:

• Hypoxia-inducible factor-1 (HIF-1)
• p300
• protein–protein interaction (PPI)
• molecular dynamics simulations
• steered molecular dynamics simulations

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Natural Science Foundation of Jilin Province (3B812C201465), National Natural Science Foundation of China (21403085). All the simulations were conducted at the High Performance Computing Center of Jilin University.