EMERGENT PROTEIN BEHAVIOR IN A CELL

Proteins must fold and function in the immensely complex environment of a cell. The interior of a cell, such as the cytoplasm, is jam-packed by macromolecules and is far from the ideal test-tube setting of a dilute solution. These macromolecules exert volume exclusion that influences the behavior of a protein. My group develops principles of protein behavior in vivo. We aim to understand the organization and dynamics of the cytoplasm, unifying the single protein scale with many-protein architectures at the subcellular scale. We apply methods grounded in statistical physics, physical modeling, and the Energy Landscape Theory to analyze the conformational variations in the ensemble of protein structures and characterize their functional output. We are currently interested in characterizing the effect of the volume exclusions or interactions from surrounding macromolecules on the distribution of protein conformations. We probe the phase diagram of a multi-domain protein under various perturbations that can be validated by experiments. We show that some protein enzymes such as phosphoglycerate kinase (PGK) might benefit from operating near a critical point by changing conformations without significant free energy cost.

 
Fig1.jpg

Structure, function and folding of phosphoglycerate kinase are strongly perturbed by macromolecular crowding

A. Dhar, A. Samiotakis, S. Ebbinghaus, L. Nienhaus, D. Homouz, M. Gruebele and M. S. Cheung, Proc Nat Acad Sci USA. 107, 17586-17591 (2010).

 
Fig2.jpg

Crowding-induced elongated conformation of urea-unfolded apoazurin explained by in silico computations: Key role of crowder shape

F. C. Zegarra, D. Homouz, A. G. Gasic, L. Babel, M. Kovermann, P. Wittung-Stafshede and M. S. Cheung, J. Phys. Chem. B, 123, 3607–3617 (2019)

 
Fig3.png

Critical phenomena in the temperature-pressure-crowding phase diagram of a protein

A. G. Gasic, M. M. Boob, M. B. Prigozhin D. Homouz, C. M. Daugherty, M. Gruebele, M. S. Cheung, Phys. Rev. X 9, 041035 (2019)