Challenges and dreams: physics of weak interactions essential to life.
Key to these properties are manifold weak "quinary" interactions that have evolved to create specific spatial networks of macromolecules.A major challenge is to develop biochemical tools and physical models to describe the panoply of weak interactions operating in cells.Partnerships between cell biologists, biochemists, and physicists are required to deploy these methods.
Affiliation: Department of Biochemistry and Molecular Biology and firstname.lastname@example.org email@example.com.
- Eukaryotic Cells/chemistry*/metabolism
- Adenosine Triphosphate/metabolism
- Cell Communication
- Models, Biological
- Phase Transition
- Protein Binding
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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).
The concentration of proteins in the bacterial cytosol reaches a staggering 250 mg/ml by some estimates (Li et al., 2014); factoring in other biological molecules (e.g., nucleic acids), the concentration of macromolecules within the cellular environment begins to reach ∼400 mg/ml, resulting in substantial loss of free water. At first glance these concentrated conditions should result in catastrophic aggregation or extremely high viscosity, yet enzyme complexes orchestrate complicated chemistry requiring free diffusion and mobility. Of interest, recent work from the Jacobs-Wagner lab has shown that under ATP-limiting conditions, the bacterial cytoplasm indeed forms a glassy state, where motions of particles are severely restricted (Figure 1A; Parry et al., 2014). In ATP-replete conditions, the cytoplasm becomes more fluid. Their work suggests that this fluidization is driven through the action of multiple energy-dependent enzymes and their dynamics, and thus the cell is investing energy to maintain cellular fluidity. This work is in excellent agreement with a prior report from the Theriot lab showing that jiggling motions of chromosomal loci in eukaryotic nuclei and in bacterial nucleoids are fueled by ATP-dependent processes (Weber et al., 2012). For both cases, increases in motion cannot be explained by a simple increase in thermal fluctuations due to heat release by energy consumption. Instead, these experiments point to a model in which energy-dependent increases in other dynamical processes drive intracellular fluidity.