Understanding the structure and dynamics of membrane proteins.
Cells have elaborate mechanisms to transport substances such as nutrients and drugs across the cell membrane that forms a barrier between the inside and outside of a cell. ATP-Binding Cassette Transporters form a large class of membrane proteins across all forms of life that play important physiological roles, including nutrient uptake in bacteria, drug resistance in cancer cells, and regulation of processes involved in cystic fibrosis and diabetes. The chemical hydrolysis of ATP, a source of energy, provides the power for ABC transporters to drive transport, but it is not clear how this common mechanism works exactly.
In this project, computer simulations on powerful parallel supercomputers are used to better understand the structural changes that occur during transport. The coupling between ATP hydrolysis, which happens in two domains outside the cell membrane, to motions inside the cell membrane is an important problem. Experimental methods have provided snapshots of structures of ABC transporters, and many experiments have provided a wealth of biochemical data. The goal of this project is to understand the mechanism of ABC transporters in more detail. This knowledge might be useful in the long term to develop more effective drug therapy in certain forms of cancer, cystic fibrosis, and other diseases related to ABC transporters.
Exploring Transport Cycle Conformational Changes
Due to the medical relevance of these transporters, detailed knowledge of the molecular basis of their mechanism of action is essential. Valentina Corradi is using computer simulations and detail-rich modeling tools to gain deeper insight into the conformational changes of transmembrane and cytosolic domains during their transport cycle.
ATP binding and hydrolysis occur on the cytosolic domains and are coupled with the conformational changes of the transmembrane domains to allow substrate translocation. Corradi’s models are used to study the dynamics of the conformational changes, and to identify transitions between different crystallographic states. Her findings will help researchers better understand the structure-function relationships of the ABC transporters as well as specific features of individual transporters, such as the human ABC transporter associated with antigen processing (TAP). TAP plays an essential role in the antigen presentation mechanism by translocating antigenic peptides from the cytosol into the endoplasmic reticulum lumen.