Computer Simulations of the Bacterial Cytoplasm

Ever since the pioneering work of Minton, it has been recognized that the highly crowded interior of biological cells has the potential to cause dramatic changes to both the kinetics and thermodynamics of protein folding and association events relative to behavior that might be observed in dilute solution conditions. One very productive way to explore the effects of crowding on protein behavior has been to use macromolecular crowding agents that exclude volume without otherwise strongly interacting with the protein under study. An alternative, complementary approach to understanding the potential differences between behavior in vivo and in vitro is to develop simulation models that explicitly attempt to model intracellular environments at the molecular scale, and that thereby can be used to directly monitor biophysical behavior in conditions that accurately mimic those encountered in vivo. It is with studies of this type that the present review will be concerned. We review in detail four published studies that have attempted to simulate the structure and dynamics of the bacterial cytoplasm and that have each explored different biophysical aspects of the cellular interior. While each of these studies has yielded important new insights, there are important questions that remain to be resolved in terms of determining the relative contributions made by energetic and hydrodynamic interactions to the diffusive behavior of macromolecules and to the thermodynamics of protein folding and associations in vivo. Some possible new directions for future generation simulation models of the cytoplasm are outlined.