Simulation of spontaneous G protein activation reveals a new intermediate driving GDP unbinding

Activation of heterotrimeric G proteins is a key step in many signaling cascades. However, a complete mechanism for this process, which requires allosteric communication between binding sites that are ~30 Å apart, remains elusive. We construct an atomically detailed model of G protein activation by combining three powerful computational methods: metadynamics, Markov state models (MSMs), and CARDS analysis of correlated motions. We uncover a mechanism that is consistent with a wide variety of structural and biochemical data. Surprisingly, the rate-limiting step for GDP release correlates with tilting rather than translation of the GPCR-binding helix 5. β-Strands 1 - 3 and helix 1 emerge as hubs in the allosteric network that links conformational changes in the GPCR-binding site to disordering of the distal nucleotide-binding site and consequent GDP release. Our approach and insights provide foundations for understanding disease-implicated G protein mutants, illuminating slow events in allosteric networks, and examining unbinding processes with slow off-rates

UV Spectral Characterization of Low-Mass Stars With AstroSat UVIT for Exoplanet Applications: The Case Study of HIP 23309

Characterizing rocky exoplanet atmospheres is a key goal of exoplanet science, but interpreting such observations will require understanding the stellar UV irradiation incident on the planet from its host star. Stellar UV mediates atmospheric escape, photochemistry, and planetary habitability, and observations of rocky exoplanets can only be understood in the context of the UV SED of their host stars. Particularly important are SEDs from observationally favorable but poorly understood low-mass M-dwarf stars, which are the only plausible targets for rocky planet atmospheric characterization for the next 1-2 decades. In this work, we explore the utility of AstroSat UVIT for the characterization of the UV SEDs of low-mass stars. We present observations of the nearby M0 star HIP 23309 in the FUV and NUV gratings of UVIT. Our FUV spectra are consistent with contemporaneous HST data and our NUV spectra are stable between orbits, suggesting UVIT is a viable tool for the characterization of the SEDs of low-mass stars. We apply our measured spectra to simulations of photochemistry and habitability for a hypothetical rocky planet orbiting HIP 23309 and elucidate the utility and limitations of UVIT in deriving UV SEDs of M-dwarf exoplanet hosts. Our work validates UVIT as a tool to complement HST in the characterization of exoplanet host stars and carries implications for its successor missions like INSIST.Comment: Accepted to A

Large Uncertainties in the Thermodynamics of Phosphorus (III) Oxide (P4_4O6_6) Have Significant Implications for Phosphorus Species in Planetary Atmospheres

Phosphorus (III) oxide (P$_4$O$_6$) has been suggested to be a major component of the gas phase phosphorus chemistry in the atmospheres of gas giant planets and of Venus. However, P$_4$O$_6$'s proposed role is based on thermodynamic modeling, itself based on values for the free energy of formation of P$_4$O$_6$ estimated from limited experimental data. Values of the standard Gibbs free energy of formation ($\Delta$Go(g)) of P$_4$O$_6$ in the literature differ by up to ~656 kJ/mol, a huge range. Depending on which value is assumed, P$_4$O$_6$ may either be the majority phosphorus species present or be completely absent from modeled atmospheres. Here, we critically review the literature thermodynamic values and compare their predictions to observed constraints on P$_4$O$_6$ geochemistry. We conclude that the widely used values from the NIST/JANAF database are almost certainly too low (predicting that P$_4$O$_6$ is more stable than is plausible). We show that, regardless of the value of $\Delta$Go(g) for P$_4$O$_6$ assumed, the formation of phosphine from P$_4$O$_6$ in the Venusian atmosphere is thermodynamically unfavorable. We conclude that there is a need for more robust data on both the thermodynamics of phosphorus chemistry for astronomical and geological modeling in general and for understanding the atmosphere of Venus and the gas giant planets in particular.Comment: Article published in ACS Earth Space Chem. https://pubs.acs.org/doi/full/10.1021/acsearthspacechem.3c0001

The Venusian Lower Atmosphere Haze as a Depot for Desiccated Microbial Life: A Proposed Life Cycle for Persistence of the Venusian Aerial Biosphere

We revisit the hypothesis that there is life in the Venusian clouds to propose a life cycle that resolves the conundrum of how life can persist aloft for hundreds of millions to billions of years. Most discussions of an aerial biosphere in the Venus atmosphere temperate layers never address whether the life-small microbial-type particles-is free floating or confined to the liquid environment inside cloud droplets. We argue that life must reside inside liquid droplets such that it will be protected from a fatal net loss of liquid to the atmosphere, an unavoidable problem for any free-floating microbial life forms. However, the droplet habitat poses a lifetime limitation: Droplets inexorably grow (over a few months) to large enough sizes that are forced by gravity to settle downward to hotter, uninhabitable layers of the Venusian atmosphere. (Droplet fragmentation-which would reduce particle size-does not occur in Venusian atmosphere conditions.) We propose for the first time that the only way life can survive indefinitely is with a life cycle that involves microbial life drying out as liquid droplets evaporate during settling, with the small desiccated 'spores' halting at, and partially populating, the Venus atmosphere stagnant lower haze layer (33-48 km altitude). We, thus, call the Venusian lower haze layer a 'depot' for desiccated microbial life. The spores eventually return to the cloud layer by upward diffusion caused by mixing induced by gravity waves, act as cloud condensation nuclei, and rehydrate for a continued life cycle. We also review the challenges for life in the extremely harsh conditions of the Venusian atmosphere, refuting the notion that the 'habitable' cloud layer has an analogy in any terrestrial environment.Comment: Open Access Astrobiology Articl

Stabilization of interdomain closure by a G protein inhibitor

Inhibitors of heterotrimeric G proteins are being developed as therapeutic agents. Epitomizing this approach are YM-254890 (YM) and FR900359 (FR), which are efficacious in models of thrombosis, hypertension, obesity, asthma, uveal melanoma, and pain, and under investigation as an FR-antibody conjugate in uveal melanoma clinical trials. YM/FR inhibits the Gq/11/14 subfamily by interfering with GDP (guanosine diphosphate) release, but by an unknown biophysical mechanism. Here, we show that YM inhibits GDP release by stabilizing closure between the Ras-like and α-helical domains of a Gα subunit. Nucleotide-free Gα adopts an ensemble of open and closed configurations, as indicated by single-molecule Förster resonance energy transfer and molecular dynamics simulations, whereas GDP and GTPγS (guanosine 5\u27-O-[gamma-thio]triphosphate) stabilize distinct closed configurations. YM stabilizes closure in the presence or absence of GDP without requiring an intact interdomain interface. All three classes of mammalian Gα subunits that are insensitive to YM/FR possess homologous but degenerate YM/FR binding sites, yet can be inhibited upon transplantation of the YM/FR binding site of Gq. Novel YM/FR analogs tailored to each class of G protein will provide powerful new tools for therapeutic investigation

Embedded Mean-Field Theory for Solution-Phase Transition-Metal Polyolefin Catalysis

Decreasing the wall-clock time of quantum mechanics/molecular mechanics (QM/MM) calculations without sacrificing accuracy is a crucial prerequisite for widespread simulation of solution-phase dynamical processes. In this work, we demonstrate the use of embedded mean-field theory (EMFT) as the QM engine in QM/MM molecular dynamics (MD) simulations to examine polyolefin catalysts in solution. We show that employing EMFT in this mode preserves the accuracy of hybrid-functional DFT in the QM region, while providing up to 20-fold reductions in the cost per SCF cycle, thereby increasing the accessible simulation time-scales. We find that EMFT reproduces DFT-computed binding energies and optimized bond lengths to within chemical accuracy, as well as consistently ranking conformer stability. Furthermore, solution-phase EMFT/MM simulations provide insight into the interaction strength of strongly coordinating and bulky counterions

Phosphine on Venus Cannot be Explained by Conventional Processes

The recent candidate detection of ~1 ppb of phosphine in the middle atmosphere of Venus is so unexpected that it requires an exhaustive search for explanations of its origin. Phosphorus-containing species have not been modelled for Venus' atmosphere before and our work represents the first attempt to model phosphorus species in the Venusian atmosphere. We thoroughly explore the potential pathways of formation of phosphine in a Venusian environment, including in the planet's atmosphere, cloud and haze layers, surface, and subsurface. We investigate gas reactions, geochemical reactions, photochemistry, and other non-equilibrium processes. None of these potential phosphine production pathways are sufficient to explain the presence of ppb phosphine levels on Venus. If PH3's presence in Venus' atmosphere is confirmed, it therefore is highly likely to be the result of a process not previously considered plausible for Venusian conditions. The process could be unknown geochemistry, photochemistry, or even aerial microbial life, given that on Earth phosphine is exclusively associated with anthropogenic and biological sources. The detection of phosphine adds to the complexity of chemical processes in the Venusian environment and motivates in situ follow up sampling missions to Venus. Our analysis provides a template for investigation of phosphine as a biosignature on other worlds.Comment: v2 is in press in Astrobiology, Special Collection: Venus; v2 also expands on the potential of phosphides from the deep mantle volcanism as a source of PH3 (as suggested by Truong and Lunine 2021: https://www.pnas.org/content/118/29/e2021689118) and shows the volcanic source of PH3 to be unlikel

Venusian phosphine:a 'Wow!' signal in chemistry?

The potential detection of ppb levels phosphine (PH3) in the clouds of Venus through millimeter-wavelength astronomical observations is extremely surprising as PH3 is an unexpected component of an oxidized environment of Venus. A thorough analysis of potential sources suggests that no known process in the consensus model of Venus' atmosphere or geology could produce PH3 at anywhere near the observed abundance. Therefore, if the presence of PH3 in Venus' atmosphere is confirmed, it is highly likely to be the result of a process not previously considered plausible for Venusian conditions. The source of atmospheric PH3 could be unknown geo- or photochemistry, which would imply that the consensus on Venus' chemistry is significantly incomplete. An even more extreme possibility is that strictly aerial microbial biosphere produces PH3. This paper summarizes the Venusian PH3 discovery and the scientific debate that arose since the original candidate detection one year ago.Comment: A short overview of the Venusian PH3 discovery and the scientific debate that arose since the original candidate detection in September 2020. Additional discussion of possible non-canonical sources of PH3 on Venus is also included. arXiv admin note: text overlap with arXiv:2009.0649