Understanding allosteric mechanisms is essential for the physical control of molecular switches and downstream cellular responses. However, it is difficult to decode essential allosteric motions in a high-throughput scheme. A general two-pronged approach to performing automatic data reduction of simulation trajectories is presented here. The first step involves coarse-graining and identifying the most dynamic residue–residue contacts. The second step is performing principal component analysis of these contacts and extracting the large-scale collective motions expressed via these residue–residue contacts. We demonstrated the method using a protein complex of nuclear receptors. Using atomistic modeling and simulation, we examined the protein complex and a set of 18 glycine point mutations of residues that constitute the binding pocket of the ligand effector. The important motions that are responsible for the allostery are reported. In contrast to conventional induced-fit and lock-and-key binding mechanisms, a novel “frustrated-fit” binding mechanism of RXR for allosteric control was revealed.

Microbial cooperation drives ecological and epidemiological processes and is affected by the ecology and demography of populations. Population density influences the selection for cooperation, with spatial structure and the type of social dilemma, namely public-goods production or self-restraint, shaping the outcome. While existing theories predict that in spatially structured environments increasing population density can select either for or against cooperation, experimental studies with both public-goods production and self-restraint systems have only ever shown that increasing population density favours cheats. We suggest that the disparity between theory and empirical studies results from experimental procedures not capturing environmental conditions predicted by existing theories to influence the outcome. Our study resolves this issue and provides the first experimental evidence that high population density can favour cooperation in spatially structured environments for both self-restraint and public-goods production systems. Moreover, using a multi-trait mathematical model supported by laboratory experiments we extend this result to systems where the self-restraint and public-goods social dilemmas interact. We thus provide a systematic understanding of how the strength of interaction between the two social dilemmas and the degree of spatial structure within an environment affect selection for cooperation. These findings help to close the current gap between theory and experiments.

Existing theory, empirical, clinical and field research all predict that reducing the virulence of individuals within a pathogen population will reduce the overall virulence, rendering disease less severe. Here, we show that this seemingly successful disease management strategy can fail with devastating consequences for infected hosts. We deploy cooperation theory and a novel synthetic system involving the rice blast fungus Magnaporthe oryzae. In vivo infections of rice demonstrate that M. oryzae virulence is enhanced, quite paradoxically, when a public good mutant is present in a population of high-virulence pathogens. We reason that during infection, the fungus engages in multiple cooperative acts to exploit host resources. We establish a multi-trait cooperation model which suggests that the observed failure of the virulence reduction strategy is caused by the interference between different social traits. Multi-trait cooperative interactions are widespread, so we caution against the indiscriminant application of anti-virulence therapy as a disease-management strategy.DOI: http://dx.doi.org/10.7554/eLife.18678.001

A special class of proteins adopts an inactive conformation in aqueous solution and activates at an interface (such as the surface of lipid droplet) by switching their conformations. Lipase, an essential enzyme for breaking down lipids, serves as a model system for studying such interfacial proteins. The underlying conformational switch of lipase induced by solvent condition is achieved through changing the status of the gated substrate-access channel. Interestingly, a lipase was also reported to exhibit pressure activation, which indicates it is drastically active at high hydrostatic pressure. To unravel the molecular mechanism of this unusual phenomenon, we examined the structural changes induced by high hydrostatic pressures (up to 1500 MPa) using molecular dynamics simulations. By monitoring the width of the access channel, we found that the protein undergoes a conformational transition and opens the access channel at high pressures (>100 MPa). Particularly, a disordered amphiphilic α5 region of the protein becomes ordered at high pressure. This positive correlation between the channel opening and α5 ordering is consistent with the early findings of the gating motion in the presence of a water-oil interface. Statistical analysis of the ensemble of conformations also reveals the essential collective motions of the protein and how these motions contribute to gating. Arguments are presented as to why heightened sensitivity to high-pressure perturbation can be a general feature of switchable interfacial proteins. Further mutations are also suggested to validate our observations. Proteins 2016; 84:820-827. © 2016 Wiley Periodicals, Inc.