The space inside living cells is highly crowded and heterogeneous, with 5–40 % of the cell volume being occupied by different biomolecules. It appears that cellular proteins have been evolutionary optimized for the environment in which they are immersed. Thus, understanding protein function requires microscopic insight into how the properties of proteins are shaped by interactions with the complex intracellular environment.
To tackle computationally the wide spread of time- and length scales involved in crowded systems, we created a multi-scale framework connecting coarse-grain and atomistic molecular dynamics simulations. This framework allowed us to investigate distinct effects of macromolecular crowding on protein stability and dynamics, and highlight the importance of weak transient interactions with the environment [1-3]. Using a computational model of a bacterial cytoplasm, we also examined changes in structural and dynamical properties of the crowded cell interior when approaching the temperature of cell death.
In this presentation, I will summarize our principal results so far, and I will outline the directions of future work aimed at elucidating the physicochemical mechanisms that underlie efficient organization of metabolic pathways inside the crowded intracellular environment. In particular, the work will focus on enzymes of the glycolytic pathway and the mechanisms of their response to changing external conditions.
(1) Gnutt, D.; Timr, S.; Ahlers, J.; Ko, B.; Manderfeld, E.; Heyden, M.; Sterpone, F.; Ebbinghaus, S. J. Am. Chem. Soc.2019, 141, 4660–4669.
(2) Timr, S.; Gnutt, D.; Ebbinghaus, S.; Sterpone, F. J. Phys. Chem. Lett.2020, 11 (10), 4206–4212.
(3) Timr, S.; Sterpone, F. J. Phys. Chem. Lett.2021, in press.