"Capturing biomolecular dynamics in the cell: making a match between modeling and experiments"
The cell is a crowded space where macromolecules, metabolites, and ions are present at high concentrations. Structural functional dynamics of these molecules spans many spatial and temporal scales. To resolve cellular events on the atomistic scale a close collaboration between experiments and modeling is needed. Here we present two research directions, united by the common theme of cell signaling in crowded environment—membrane-associated phenomena and in-cell protein dynamics—where our multiscale modeling and experiments by our collaborators are used in synergy. On the membrane efforts, we describe how divalent calcium ions shape functional dynamics of anionic lipids that is critical to signaling and present structural dynamic ensembles of cholesterol in the membrane that revealed unexpected features. On the in-cell direction, we demonstrate that in our E. coli cytoplasm model the transient nonfunctional protein-protein interactions have a very short half-life (~1 μs), which hints at the proteome co-evolution to prevent sticking. We then contrast the dynamics of the phosphoglycerate kinase (PGK)—glycolytic enzyme conserved across three Domains of Life—in dilute solution with that in a mammalian cytoplasm model. We captured that from three functional hinge-bending states of PGK— open, semi-open, and closed—only two are populated in-vitro while all three are present in our in-cell model,
underscoring cytoplasm influence. Our work shows dramatic influence of cellular environments on dynamics of proteins and will guide future theoretical and experimental investigations.