Challenges and dreams: physics of weak interactions essential to life

Abstract

Biological systems display stunning capacities to self-organize. Moreover, their subcellular architectures are dynamic and responsive to changing needs and conditions. Key to these properties are manifold weak "quinary" interactions that have evolved to create specific spatial networks of macromolecules. These specific arrangements of molecules enable signals to be propagated over distances much greater than molecular dimensions, create phase separations that define functional regions in cells, and amplify cellular responses to changes in their environments. A major challenge is to develop biochemical tools and physical models to describe the panoply of weak interactions operating in cells. We also need better approaches to measure the biases in the spatial distributions of cellular macromolecules that result from the integrated action of multiple weak interactions. Partnerships between cell biologists, biochemists, and physicists are required to deploy these methods. Together these approaches will help us realize the dream of understanding the biological "glue" that sustains life at a molecular and cellular level.

FIGURE 1:

(A) Local energy consumption modulates global cellular dynamics. Proteins are constantly undergoing conformational changes (squares/circles) and breathing (wavy lines). In many cases these dynamics are fueled directly by energy consumption (e.g., conformational changes in AAA+ proteins) or indirectly (e.g., client protein remodeling by ATP-dependent chaperones). As illustrated in the work of Parry et al. (2014), in the absence of ATP, these interactions may be dampened, freezing proteins into static conformations. At the high solute concentrations in the cell, weak quinary interactions between these proteins can force a phase transition into a more “glass-like” state. On restoration of ATP, motions resume, breaking these weak interactions and fluidizing the entire pool of cellular biomolecules. (B) Formation of large-scale biomolecule assemblies can occur with a collection of weakly interacting proteins. At low concentrations, RNA and weakly interacting proteins circulate freely. At higher concentrations or higher valency, weak interactions cooperate to generate a higher-order assembly (Li et al., 2012). In the case of RNA granules, low-complexity regions within multiple proteins produce a dynamic hydrogel that cages RNA (Han et al., 2012). Hydrogels can be disassembled rapidly upon phosphorylation of the proteins (as shown by yellow circles) or by changes in temperature and concentration (Kato et al., 2012). (C) Transient short-range interactions can tune long-range effects across the cell. Proper incorporation of peptidoglycan monomers into bacterial cell envelopes requires cross-linking enzymes (red) recruited by a moving assembly platform (gray). At high concentrations (left), there are sufficient cross-linking enzymes to saturate the platforms. If the interaction of cross-linking enzymes with the platform is strong/stable, then a decrease in enzyme levels would result in regions that lack the cross-linking enzyme and thus are unable to add monomers. Over a long enough time interval (Δt), this would result in loss of cell wall integrity at those unfulfilled points. By contrast, dynamic weak interactions enable transient association of cross-linking enzymes with platforms and thus buffer changes in enzyme concentration so as to sustain cell-wide synthesis by rapid redistribution of enzymes across many platforms (Lee et al., 2014).