Research Projects

Parallel Tempering or Replica Exchange methods such as REMD and Replica Exchange with Solute Tempering (REST2, gREST) have been used successfully to study protein folding pathways. But, exploring the conformation landscape of IDPs had been a tricky problem until recently. My group recently showed an excellent sampling of IDPs using their Replica Exchange with Hybrid Tempering (REHT) method and could convincingly match the experimental SAXS and NMR data (Nature Communication, 2021, https://doi.org/10.1038/s41467-021-21105-7). In this method, the differential and optimal heating of both the protein (solute) and water (solvent) lead to crossing large free energy and entropic barriers. Hence, the IDPs could escape metastable states quickly and explore all conformational basins. Although REHT could explore the conformational landscape of an IDP in solution well, they have not been tested in the context of the membrane. Also, the folding of IDPs on the membrane may be strewn with metastable states and large entropic barriers. These problems could be overcome using REHT in the context of the membrane. Researchers will use this grant to extend the REHT method so that peptide folding in membrane can be explored and the underlying mechanism unravelled for therapeutic design purposes.