Executive Summary : | Proteins are required to fold in their native structure to perform the desired cellular functions. However, sometimes a protein can misfold by acquiring a non-native structure. Misfolded proteins may function with a reduced efficiency or do not perform any function at all. To avoid this, a class of chaperones assists the folding of proteins in their native structure at the expense of energy released from the hydrolysis of ATP molecules. Experiments have unraveled various kinetic and structural details of such chaperones’ action of protein folding. However, what remains missing is the fundamental theoretical understanding of its operational mechanisms, especially the limits and constraints imposed on its efficiency by the energy flow and dissipation. Therefore, using the tools of non-equilibrium physics, Project proposes studying how energy expenditure shapes chaperones’ efficiency to fold (in the native structure)/unfold the misfolded proteins. This proposal also plans to understand various tradeoffs of the efficiency of chaperone action with its speed, energy dissipation, and other metabolic costs. Such physics-based constraints on chaperone efficiency must have some biological consequences as well. Therefore, PI shall also explore the biological implications of fundamental theoretical bounds of chaperones’ efficiency and speed-efficiency-energy dissipation tradeoffs on protein folding. Such analyses will enable us to understand what makes a good chaperone. The proposed study would improve our fundamental understanding of a biological process that plays a vital role in maintaining proteome health and contributes to a significant amount of the cellular energy expenditure. |