Welcome to darlintai Lab!

The main focus of our group is to use both computational tools and experimental methods to investigate the recognition mechanisms between proteins and their specific DNA targets, i.e., how does the protein proceed to search for the target sites along the DNA chains? How does the DNA shape might affect the protein binding? How does the protein locate its specific DNA sequence among vast amounts of resembling DNA motifs etc? The ongoing projects in our lab are detailed as follows:

1. Computational investigations on the target-site searching and recognition mechanism by DNA glycosylase

DNA glycosylase, as one member of the DNA repair machineries, plays an essential role in correcting mismatched/damaged DNA base pair by cleaving the N-glycosidic bond between the sugar and target base through the base excision repair (BER) pathways. Efficient corrections of these DNA lesions are critical for maintaining genome integrity and preventing premature aging and cancer. Therefore, an atomistic-level understanding of the dynamics of the DNA glycosylase involved in the DNA repair process can provide deep insights into the development of novel anti-cancer drugs. The target-site searching and recognition mechanism by DNA glycosylase, however, remains unknown and experimental characterization of the above process is still challenging due to the limited spatiotemporal resolutions. By employing high performance computing, combined with markov state model construction based on extensive all-atom molecular dynamics (MD) simulations, our group is currently focused on two critical human DNA glycosylases, namely thymine DNA glycosylase (TDG) and alkyladenine DNA glycosylase (AAG), regarding their target searching and substrate-recognition mechanisms. We expect to reveal the key intermediates of the above two DNA glycosylases involved in the DNA repair process. Finally, the captured intermediate states can be used as potential drug targets for future guidance to design novel anti-cancer drugs.

2. Computational investigations on the dynamics of the HIV envelope trimer during membrane fusion

During the HIV entry, membrane fusion of the HIV and host cells is the first step and driven mainly by the glycoproteins gp120 and gp41 that form a trimer on the surface of the HIV envelope. Therefore, the gp120-gp41 complex is an important drug target to design HIV inhibitors and precursors for the HIV vaccine. However, the underlying mechanisms and atomistic-level understandings of the conformational changes of the gp120-gp41 complex induced by its receptor CD4 and co-receptors CCR5 or CXCR4 are still lack of. In current project, we are focused on investigating the dynamics of the gp120 in both its monomer and trimer state after its binding to CD4 and the refolding mechanisms of the gp41 by combining with high throughput computing, molecular dynamics simulations and Markov State Model (MSM). We expect to capture the key intermediate state of both gp120 and gp41, as well as their associated thermodynamic and kinetic properties. Finally, the above observed intermediate states can be used as potential drug targets for future structure-based anti-HIV drug discovery to design new-scaffold HIV inhibitors with high antivirus activities. In addition, our results will provide new insights for designing novel HIV vaccines that is capable of eliciting broadly neutralizing antibodies.