Biasing the quantum vacuum to control macroscopic probability distributions

One of the most important insights of quantum field theory is that electromagnetic fields must fluctuate. Even in the vacuum state, the electric and magnetic fields have a nonzero variance, leading to ubiquitous effects such as spontaneous emission, the Lamb shift, the Casimir effect, and more. These "vacuum fluctuations" have also been harnessed as a source of perfect randomness, for example to generate perfectly random photonic bits. Despite these achievements, many potential applications of quantum randomness in fields such as probabilistic computing rely on controllable probability distributions, which have not yet been realized on photonic platforms. In this work, we show that the injection of vacuum-level "bias" fields into a multi-stable optical system enables a controllable source of "biased" quantum randomness. We demonstrate this concept in an optical parametric oscillator (OPO). Ordinarily, an OPO initiated from the ground state develops a signal field in one of two degenerate phase states (0 and $\pi$) with equal probability. By injecting bias pulses which contain less than one photon on average, we control the probabilities associated with the two output states, leading to the first controllable photonic probabilistic bit (p-bit). We shed light on the physics behind this process, showing quantitative agreement between theory and experiment. Finally, we demonstrate the potential of our approach for sensing sub-photon level fields by showing that our system is sensitive to the temporal shape of bias field pulses far below the single photon level. Our results suggest a new platform for the study of stochastic quantum dynamics in nonlinear driven-dissipative systems, and point toward possible applications in ultrafast photonic probabilistic computing, as well as the sensing of extremely weak fields

Xenoprotein engineering via synthetic libraries

Chemical methods have enabled the total synthesis of protein molecules of ever-increasing size and complexity. However, methods to engineer synthetic proteins comprising noncanonical amino acids have not kept pace, even though this capability would be a distinct advantage of the total synthesis approach to protein science. In this work, we report a platform for protein engineering based on the screening of synthetic one-bead one-compound protein libraries. Screening throughput approaching that of cell surface display was achieved by a combination of magnetic bead enrichment, flow cytometry analysis of on-bead screens, and high-throughput MS/MS-based sequencing of identified active compounds. Direct screening of a synthetic protein library by these methods resulted in the de novo discovery of mirror-image miniprotein-based binders to a ∼150-kDa protein target, a task that would be difficult or impossible by other means. Keywords: xenoprotein; mirror-image miniprotein; D-protein; protein engineering; flow cytometryUnited States. Defense Advanced Research Projects Agency (Award 023504-001

An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism

Abstract GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation