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Abstract The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular dynamics (MD) simulations in dilute as well as crowded protein solution. The populations of the inhibitor, 4-amino-5-(4-methylphenyl)−7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), in bulk solution and on the surface of c-Src kinase are reduced as the concentration of crowder bovine serum albumins (BSAs) increases. This observation is consistent with the reduced PP1 inhibitor efficacy in experimental c-Src kinase assays in addition with BSAs. The crowded environment changes the major binding pathway of PP1 toward c-Src kinase compared to that in dilute solution. This change is explained based on the population shift mechanism of local conformations near the inhibitor binding site in c-Src kinase. 

Phase separation processes are increasingly being recognized as important organizing mechanisms of biological macromolecules in cellular environments. Well-established drivers of phase separation are multi-valency and intrinsic disorder. Here, we show that globular macromolecules may condense simply based on electrostatic complementarity. More specifically, phase separation of mixtures between RNA and positively charged proteins is described from a combination of multiscale computer simulations with microscopy and spectroscopy experiments. Phase diagrams were mapped out as a function of molecular concentrations in experiment and as a function of molecular size and temperature via simulations. The resulting condensates were found to retain at least some degree of internal dynamics varying as a function of the molecular composition. The results suggest a more general principle for phase separation that is based primarily on electrostatic complementarity without invoking polymer properties as in most previous studies. Simulation results furthermore suggest that such phase separation may occur widely in heterogenous cellular environment between nucleic acid and protein components. 

ABSTRACT In this article, I describe a new curriculum for introductory physics for the life sciences, a 2-semester sequence usually required of all biology majors. Because biology-related applications on the macroscale are complex and require mathematics beyond introductory calculus, the focus is entirely on applications from molecular and cellular biology. Topics that are more relevant for engineering have been removed, and topics relevant to biology have been added. The curriculum is designed around 2 main themes: diffusion and electric dipoles. Diffusion illustrates the concepts of conservation of momentum and energy and provides the framework for introducing entropy from the perspective of statistical mechanics. Electric dipoles illustrate the basic concepts of electromagnetic theory and provide the framework for understanding light waves and light interactions with biomolecules. These themes are supported by small computational activities to help students understand the physics without advanced mathematics. This curriculum has been piloted over the past 4 years at Michigan State University and should be applicable to many colleges and universities.