Protein folding and the robustness of cells

The intricate intracellular infrastructure of all known life forms is based on proteins. The folded shape of a protein determines both the protein’s function and the set of molecules it will bind to. This tight coupling between a protein’s function and its interconnections in the molecular interaction network has consequences for the molecular course of evolution. It is also counter to human engineering approaches. Here we report on a simulation study investigating the impact of random errors in an abstract metabolic network of 500 enzymes. Tight coupling between function and interconnectivity of nodes is compared to the case where these two properties are independent. Our results show that the model system under consideration is more robust if function and interconnection are intertwined. These findings are discussed in the context of nanosystems engineering

Self-organization of intrinsically disordered proteins with folded N-termini

Thousands of human proteins lack recognizable tertiary structure in most of their chains. Here we hypothesize that some use their structured N-terminal domains (SNTDs) to organise the remaining protein chain via intramolecular interactions, generating partially structured proteins. This model has several attractive features: as protein chains emerge, SNTDs form spontaneously and serve as nucleation points, creating more compact shapes. This reduces the risk of protein degradation or aggregation. Moreover, an interspersed pattern of SNTD-docked regions and free loops can coordinate assembly of sub-complexes in defined loop-sections and enables novel regulatory mechanisms, for example through posttranslational modifications of docked regions

Evolution favors protein mutational robustness in sufficiently large populations

BACKGROUND: An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual, but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. RESULTS: Here we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by existing mathematical theories, and can be quantitatively related to the way that the proteins occupy their neutral network. CONCLUSIONS: Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon may contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations