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We introduce ChemPro, a progressive benchmark with 4100 natural language question-answer pairs in Chemistry, across 4 coherent sections of difficulty designed to assess the proficiency of Large Language Models (LLMs) in a broad spectrum of general chemistry topics. We include Multiple Choice Questions and Numerical Questions spread across fine-grained information recall, long-horizon reasoning, multi-concept questions, problem-solving with nuanced articulation, and straightforward questions in a balanced ratio, effectively covering Bio-Chemistry, Inorganic-Chemistry, Organic-Chemistry and Physical-Chemistry. ChemPro is carefully designed analogous to a student's academic evaluation for basic to high-school chemistry. A gradual increase in the question difficulty rigorously tests the ability of LLMs to progress from solving basic problems to solving more sophisticated challenges. We evaluate 45+7 state-of-the-art LLMs, spanning both open-source and proprietary variants, and our analysis reveals that while LLMs perform well on basic chemistry questions, their accuracy declines with different types and levels of complexity. These findings highlight the critical limitations of LLMs in

Earth's surface is deficient in available forms of many elements considered limiting for prebiotic chemistry. In contrast, many extraterrestrial rocky objects are rich in these same elements. Limiting prebiotic ingredients may, therefore, have been delivered by exogenous material; however, the mechanisms by which exogeneous material may be reliably and non-destructively supplied to a planetary surface remains unclear. Today, the flux of extraterrestrial matter to Earth is dominated by fine-grained cosmic dust. Although this material is rarely discussed in a prebiotic context due to its delivery over a large surface area, concentrated cosmic dust deposits are known to form on Earth today due to the action of sedimentary processes. Here we combine empirical constraints on dust sedimentation with dynamical simulations of dust formation and planetary accretion to show that localized sedimentary deposits of cosmic dust could have accumulated in arid environments on early Earth, in particular glacial settings that today produce cryoconite sediments. Our results challenge the widely held assumption that cosmic dust is incapable of fertilizing prebiotic chemistry. Cosmic dust deposits may

The present study aims at characterizing the habitability conditions of exoplanets with an Earth-like magnetosphere inside the habitable zone of M stars and F stars like tau Boo, caused by the direct deposition of the stellar wind on the exoplanet surface if the magnetosphere shielding is inefficient. In addition, the radio emission generated by exoplanets with a Earth-like magnetosphere is calculated for different space weather conditions. The study is based on a set of MHD simulations performed by the code PLUTO reproducing the space weather conditions expected for exoplanets orbiting the habitable zone of M stars and F stars type tau Boo. Exoplanets hosted by M stars at 0.2 au are protected from the stellar wind during regular and CME-like space weather conditions if the star rotation period is slower than 3 days, that is to say, faster rotators generate stellar winds and interplanetary magnetic fields large enough to endanger the exoplanet habitability. Exoplanets hosted by a F stars type tau Boo at >= 2.5 au are protected during regular space weather conditions, but a stronger magnetic field compared to the Earth is mandatory if the exoplanet is close to the inner edge of t

The emergence of life on the Earth has required a prior organic chemistry leading to the formation of prebiotic molecules. The origin and the evolution of the organic matter on the early Earth is not yet firmly understood. Several hypothesis, possibly complementary, are considered. They can be divided in two categories: endogenous and exogenous sources. In this work we investigate the contribution of a specific endogenous source: the organic chemistry occurring in the ionosphere of the early Earth where the significant VUV contribution of the young Sun involved an efficient formation of reactive species. We address the issue whether this chemistry can lead to the formation of complex organic compounds with CO2 as only source of carbon in an early atmosphere made of N2, CO2 and H2, by mimicking experimentally this type of chemistry using a low pressure plasma reactor. By analyzing the gaseous phase composition, we strictly identified the formation of H2O, NH3, N2O and C2N2. The formation of a solid organic phase is also observed, confirming the possibility to trigger organic chemistry in the upper atmosphere of the early Earth. The identification of Nitrogen-bearing chemical functio

The Earth's magnetosphere is formed as a consequence of interaction between the planet's magnetic field and the solar wind, a continuous plasma stream from the Sun. A number of different solar wind phenomena have been studied over the past forty years with the intention of understanding and forecasting solar behavior. One of these phenomena in particular, Earth-bound interplanetary coronal mass ejections (CMEs), can significantly disturb the Earth's magnetosphere for a short time and cause geomagnetic storms. This publication presents a mission concept consisting of six spacecraft that are equally spaced in a heliocentric orbit at 0.72 AU. These spacecraft will monitor the plasma properties, the magnetic field's orientation and magnitude, and the 3D-propagation trajectory of CMEs heading for Earth. The primary objective of this mission is to increase space weather (SW) forecasting time by means of a near real-time information service, that is based upon in-situ and remote measurements of the aforementioned CME properties. The mission's secondary objective is to provide vital data to update scientific models. In-situ measurements are performed using a Solar Wind Analyzer instrumenta

This article investigates long-term orbits within the Earth's magnetosphere, specifically focusing on orbits where the argument of periapsis is synchronized with changes induced by lunar gravity assists and the Earth's argument of latitude over a complete orbital period in Earth-Moon resonance. In the Earth-Moon rotating frame, resonance orbits appear repetitive; however, the argument of periapsis shifts due to the third-body effects from lunar flybys. The extent of this shift is influenced by the Jacobi integral associated with the resonance orbit. To identify feasible resonance orbits and the optimal Jacobi integral, we map the argument of periapsis change against the Jacobi integral for each prospective orbit. This synchronization allows the spacecraft to remain within a confined region in space when observed from the Sun-Earth rotating frame. Finally, the article discusses the applications of these long-term Earth magnetosphere science orbits, including orbit-orientation reconfiguration (station keeping) and stability.

The bulk silicate Earth (BSE) is depleted in moderately volatile elements, indicating Earth formed from a mixture of volatile-rich and -poor materials. To better constrain the origin and nature of Earth's volatile-rich building blocks, we determined the mass-dependent isotope compositions of Ge in carbonaceous (CC) and enstatite chondrites. We find that, similar to other moderately volatile elements, the Ge isotope variations among the chondrites reflect mixing between volatile-rich, isotopically heavy matrix and volatile-poor, isotopically light chondrules. The Ge isotope composition of the BSE is within the chondritic range and can be accounted for as a ~2:1 mixture of CI and enstatite chondrite-derived Ge. This mixing ratio appears to be distinct from the ~1:2 ratio inferred for Zn, reflecting the different geochemical behavior of Ge (siderophile) and Zn (lithophile), and suggesting the late-stage addition of volatile-rich CC materials to Earth. On dynamical grounds it has been argued that Earth accreted CC material through a few Moon-sized embryos, in which case the Ge isotope results imply that these objects were volatile-rich, presumably because they were either undifferentia

We present a model for lightning shock induced chemistry that can be applied to atmospheres of arbitrary H/C/N/O chemistry, hence for extrasolar planets and brown dwarfs. The model couples hydrodynamics and the STAND2015 kinetic gas-phase chemistry. For an exoplanet analogue to the contemporary Earth, our model predicts NO and NO2 yields in agreement with observation. We predict height-dependent mixing ratios during a storm soon after a lightning shock of NO ~ 1e-3 at 40 km and NO2 ~ 1e-4 below 40 km, with O3 reduced to trace quantities (<< 1e-10). For an Earth-like exoplanet with a CO2/N2 dominated atmosphere and with an extremely intense lightning storm over its entire surface, we predict significant changes in the amount of NO, NO2, O3, H2O, H2, and predict significant abundance of C2N. We find that, for the Early Earth, O2 is formed in large quantities by lightning but is rapidly processed by the photochemistry, consistent with previous work on lightning. The effect of persistent global lightning storms are predicted to be significant, primarily due to NO2, with the largest spectral features present at ~3.4 μm and ~6.2 μm. The features within the transmission spectrum are

In this chapter we describe chemistry of the early atmosphere of the Earth during and shortly after its formation where there is little if any geological record. We review the arguments for a secondary origin of the terrestrial atmosphere, that is by outgassing during and/or after accretion rather than by capture of solar nebula gas. Then we discuss sources of volatiles accreted by the Earth using meteorites as analogs for the material present in the solar nebula. The next section reviews heating during accretion of the Earth. Subsequently we describe chemistry of the silicate vapor, steam, and gaseous stages of atmospheric evolution on the early Earth. We close with a summary of the key questions that remain unresolved.

We present a community-wide effort to develop a strategy and action plan to advance heliophysics and space weather modeling through open science. While open science has the potential to enhance the quality and pace of scientific discovery, its application to scientific modeling requires more careful consideration regarding open data and open software guidelines, as scientific models differ significantly from data analysis software. We gathered feedback from modeling teams worldwide through a living survey and discussion sessions at the 2024 Open Science Workshop in College Park, USA, and at the 2025 COSPAR ISWAT Working Meeting in Cape Canaveral, USA. We complement these findings with lessons learned from almost 25 years of experience at the Community Coordinated Modeling Center in enabling open use of models. We identify key roadblocks in current open science practices and guidelines and offer recommendations for future progress across four overlapping themes: open use of models and simulation results, open validation, open development, and open collaboration. An essential outcome of the discussion is the need for model developers and model users to speak with a united voice and p

The spatial distribution of the chemical reservoirs in protoplanetary disks is key to elucidate the composition of planets, especially habitable ones. However, the partitioning of the main elements among the refractory and volatile phases is still elusive. Key parameters such as the carbon-to-oxygen C/O elemental ratio and the ionization fraction remain poorly constrained, with the latter potentially orders of magnitude lower than in the interstellar medium. Moreover, the thermal structure of the gas is also poorly known, despite its deep influence on gas-phase chemistry. In this context, ortho-to-para ratios could provide selective and sensitive probes. Recent ALMA observations have measured the spatially resolved column density of ortho-and para-H2CO in the transition disk orbiting TW Hya and derived the radial profile of the ortho-to-para ratio. Yet, current disk models do not include the nuclear-spin-resolved chemistry required to interpret these observations. The present work aims to fill this gap, by combining a parametric disk physical model of TW Hya with the UGAN network, updated to include a comprehensive description of the nuclear-spin-resolved chemistry of formaldehyde.

Multimodal scientific reasoning remains a significant challenge for large language models (LLMs), particularly in chemistry, where problem-solving relies on symbolic diagrams, molecular structures, and structured visual data. Here, we systematically evaluate 40 proprietary and open-source multimodal LLMs, including GPT-5, o3, Gemini-2.5-Pro, and Qwen2.5-VL, on a curated benchmark of Olympiad-style chemistry questions drawn from over two decades of U.S. National Chemistry Olympiad (USNCO) exams. These questions require integrated visual and textual reasoning across diverse modalities. We find that many models struggle with modality fusion, where in some cases, removing the image even improves accuracy, indicating misalignment in vision-language integration. Chain-of-Thought prompting consistently enhances both accuracy and visual grounding, as demonstrated through ablation studies and occlusion-based interpretability. Our results reveal critical limitations in the scientific reasoning abilities of current MLLMs, providing actionable strategies for developing more robust and interpretable multimodal systems in chemistry. This work provides a timely benchmark for measuring progress in

One in every two atoms in the Earth, Mars, and the Moon is oxygen; it is the third most abundant element in the solar system. The oxygen isotopic compositions of the terrestrial planets are different from those of the Sun and demonstrate that these planets are not direct compositional analogs of the solar photosphere. Likewise, the Suns O/Fe, Fe/Mg and Mg/Si values are distinct from those of inner solar system chondrites and terrestrial planets. These four elements (O, Fe, Mg, Si) make up about 94% by mass of the rocky planets and their abundances are determined uniquely using geophysical, geochemical and cosmochemical constraints. The rocky planets grew rapidly from planetesimals, most of which were differentiated, having a core and a mantle, before being accreted. Planetary growth in the early stages of protoplanetary disk evolution was rapid and was only partially recorded by the meteoritic record. The noncarbonaceous meteorites (NC) provide insights into the early history of the inner solar system and are used to construct a framework for how the rocky planets were assembled. NC chondrites have chondrule ages that are two to three million years younger than t_zero (the age of c

The Malaysian satellite RazakSAT-1 was designed to operate in a near-equatorial orbit (NEqO) and low earth orbit (LEO). However, after one year of operation in 2010, communication to the satellite was lost. This study attempted to identify whether space radiation sources could have caused the communication loss by comparing RazakSAT-1 with two functional satellites. Data on galactic cosmic rays (GCR), trapped protons, trapped electrons, and solar energetic particles (SEPs) obtained from Space Environment Information System (SPENVIS) was analyzed.

The search for extrasolar Earth-like planets is underway. Over 100 extrasolar giant planets are known to orbit nearby sun-like stars, including several in multiple-planet systems. These planetary systems are stepping stones for the search for Earth-like planets; the technology development, observational strategies, and science results can all be applied to Earth-like planets. Stars much less massive than the sun the most common stars in our Galaxy are being monitored for the gravitational influence of Earth-like planets. Although Earth-like planets orbiting sun-like stars are much more difficult to detect, space missions are being built to detect them indirectly due to their effects on the parent star and to quantify fundamental factors such as terrestrial planet frequency, size distribution, and mass distribution. Extremely ambitious space programs are being developed to directly detect Earth-like planets orbiting sun-like stars, and must tackle the immense technological challenge of blocking out the light of the parent star, which is brighter than the planet by six to ten orders of magnitude. Direct detection of radiation from the planet is necessary for the definitive goal of th

The CHaracterising ExOPlanet Satellite (CHEOPS) is a partnership between the European Space Agency and Switzerland with important contributions by 10 additional ESA member States. It is the first S-class mission in the ESA Science Programme. CHEOPS has been flying on a Sun-synchronous low Earth orbit since December 2019, collecting millions of short-exposure images in the visible domain to study exoplanet properties. A small yet increasing fraction of CHEOPS images show linear trails caused by resident space objects crossing the instrument field of view. To characterize the population of satellites and orbital debris observed by CHEOPS, all and every science images acquired over the past 3 years have been scanned with a Hough transform algorithm to identify the characteristic linear features that these objects cause on the images. Thousands of trails have been detected. This statistically significant sample shows interesting trends and features such as an increased occurrence rate over the past years as well as the fingerprint of the Starlink constellation. The cross-matching of individual trails with catalogued objects is underway as we aim to measure their distance at the time of

Astronomical solutions provide calculated orbital and rotational parameters of solar system bodies based on the dynamics and physics of the solar system. Application of astronomical solutions in the Earth sciences has revolutionized our understanding in at least two areas of active research. (i) The Astronomical (or Milankovic) forcing of climate on time scales > ~10 kyr and (ii) the dating of geologic archives. The latter has permitted the development of the astronomical time scale, widely used today to reconstruct highly accurate geological dates and chronologies. The tasks of computing vs. applying astronomical solutions are usually performed by investigators from different backgrounds, which has led to confusion and recent inaccurate results on the side of the applications. Here we review astronomical solutions and Milankovic forcing in the Earth sciences, primarily aiming at clarifying the astronomical basis, applicability, and limitations of the solutions. We provide a summary of current up-to-date and outdated astronomical solutions and their valid time span. We discuss the fundamental limits imposed by dynamical solar system chaos on astronomical calculations and geologi

The national space programs have an historic opportunity to help solve the global-scale economic and environmental problems of Earth while becoming more effective at science through the use of space resources. Space programs will be more cost-effective when they work to establish a supply chain in space, mining and manufacturing then replicating the assets of the supply chain so it grows to larger capacity. This has become achievable because of advances in robotics and artificial intelligence. It is roughly estimated that developing a lunar outpost that relies upon and also develops the supply chain will cost about 1/3 or less of the existing annual budgets of the national space programs. It will require a sustained commitment of several decades to complete, during which time science and exploration become increasingly effective. At the end, this space industry will capable of addressing global-scale challenges including limited resources, clean energy, economic development, and preservation of the environment. Other potential solutions, including nuclear fusion and terrestrial renewable energy sources, do not address the root problem of our limited globe and there are real questio

Tailor-made: Discussed herein is the ability to adapt biology's mechanisms for innovation and optimization to solving problems in chemistry and engineering. The evolution of nature's enzymes can lead to the discovery of new reactivity, transformations not known in biology, and reactivity inaccessible by small-molecule catalysts. In this competitive age, when new industries sprout and decay in the span of a decade, we should reflect on how a company survives to celebrate its 350th anniversary. A prerequisite for survival in business is the ability to adapt to changing environments and tastes, and to sense, anticipate, and meet needs faster and better than the competition. This requires constant innovation as well as focused attention to execution. A company that continues to provide meaningful and profitable solutions to human problems has a chance to survive, even thrive, in a rapidly changing and highly competitive world. Biology has a brilliant algorithm for solving the problem of survival over time: evolution. Those who adapt and (re)produce outcompete the less agile and less fertile. Over the last 30 years—which seems a long time but is less than one-tenth the time Merck KGaA, Darmstadt, Germany has been in business—I have tried to adapt biology's mechanisms for innovation and optimization to solving problems in chemistry and engineering. It turns out that evolution is a powerful forward-engineering process, whose widespread adoption in enzyme engineering and synthetic biology has been made possible through advances in molecular biology and high-throughput screening. Nature, the best chemist of all time, solves the difficult problem of being alive and enduring for billions of years, under an astonishing range of conditions. Most of the marvelous chemistry that makes life possible is the work of nature's macromolecular protein catalysts, the enzymes. By using enzymes, nature can extract materials and energy from the environment and convert them into self-replicating, self-repairing, mobile, adaptable, and sometimes even thinking biochemical systems. These systems are good models for a sustainable chemical industry that uses renewable resources and recycles a good fraction of its products. And biology is not just a model from which to draw inspiration: living organisms or their components can be efficient production platforms. In fact, I predict that DNA-programmable microorganisms will be producing many of our chemicals in the not-so-distant future. That most chemicals are made using synthetic processes starting from petroleum-based feedstocks reflects the remarkable creativity of synthetic chemists in developing reaction schemes and catalysts that nature never discovered. Synthetic chemistry has given us an explosion of products, which feed, clothe, house, entertain, and cure us. Synthetic chemistry, however, struggles to match the efficiency and selectivity that biology achieves with enzymes. In many cases, synthetic processes rely on precious metals, toxic reagents and solvents, and extreme conditions, and they generate substantial amounts of unwanted byproducts. DNA-programmable chemical synthesis using enzymes promises to improve on synthetic chemistry, particularly if we are able to expand biology's catalytic repertoire to include some of the most synthetically useful reactions, under physiological conditions and with earth-abundant resources. Such clean, green chemistry might sound like pie in the sky, but enzymes already show how a protein can orient substrates for reaction, exclude water from an active site, activate a metal or simple organic cofactor, or suppress competing reactions to draw out new and admirable synthetic capabilities. Synthetic chemists have been drawing inspiration from biology for decades, and now is the time for protein engineers to use inspiration from synthetic chemistry to generate new enzymes that will improve on and replace synthetic catalysts and reaction pathways.1 Unfortunately, our understanding of the link between sequence and function lags well behind our desire for new enzymes. Given that our ability to predict protein sequences, or even just changes to a sequence, which reliably give rise to whole new, finely tuned catalytic activities is rudimentary at best, creating new enzymes capable of improving on current synthetic processes is a pretty tall order. We also dream of going beyond known chemistry to create enzymes that catalyze reactions or make products that are simply not possible with any known method, synthetic or otherwise. Requiring that these new enzymes assemble and function in cells, where they can be made at low cost and incorporated into synthetic metabolic pathways to generate a broader array of products, represents an even greater set of engineering constraints and challenges. Nature's enzymes are the products of evolution, not design. By using generations of mutation and selection for fitness advantages, evolution allows organisms to continuously update and optimize their enzyme repertoires. New enzymes even appear in real time in response to challenges (e.g. the need to resist antibiotics or pesticides) or opportunities (e.g. the chance to occupy a new food niche by degrading recently introduced, manmade substances). I argue that the process that gave rise to all the remarkable biological catalysts in nature should be able to produce yet more. In the laboratory. Quickly. Advances in molecular biology over the past few decades—the ability to write, cut, and paste DNA and to have that DNA read and translated into proteins in recombinant organisms—have given us the ability to breed enzymes much like we breed sheep or sake yeast. We can direct the evolution of enzymes in the laboratory by requiring them to perform in ways that may not be useful to a bacterium but are useful to us. Directed evolution achieves these desirable functional outcomes while circumventing our deep ignorance of how sequence encodes them. Directed evolution mimics evolution by artificial selection, and is accelerated in the laboratory setting by focusing on individual genes expressed in fast-growing microorganisms. We start with existing proteins (sourced from nature or engineered), introduce mutations, and then screen for the progeny proteins with enhanced activity (or another desirable trait). We use the improved enzymes as parents for the next round of mutation and screening, recombining beneficial mutations as needed, and continuing until we reach the target level of performance. Engineering enzymes in the 1980s and 1990s, I learned the hard way that there was no reliable method to predict performance-enhancing mutations. Turning instead to random mutagenesis and screening, I quickly realized that such mutations were easy to find and accumulate with the right evolutionary optimization strategy. My students and I observed that proteins, the products of evolution, are themselves readily evolvable. Properties we and others targeted in the early days of directed evolution (the mid-1990s) included recovering activity in unusual environments (e.g. organic solvents), improving activity on non-native substrates, enhancing thermostability, and changing enantioselectivity. We learned the then-surprising fact that beneficial mutations could be far from an active site, and often appeared on the protein surface (which in those days was generally deemed insensitive to mutation and functionally neutral). To this day, no one can explain satisfactorily how such mutations exert their effects, much less predict them. Although we could enhance activity (and many other properties) by accumulating beneficial mutations over generations of random mutagenesis and screening, evolving a whole new catalytic activity seemed a much more difficult problem. After all, evolution is not good for problems that require multiple, simultaneous, low-probability events,2 and the active sites of enzymes are so beautifully and precisely configured that it was hard to imagine how the stepwise accumulation of beneficial mutations could create a new one. Evolution's innovation mechanisms, however, are more simple than they might appear: evolution works best when it does not need to generate a whole new active site from scratch. Instead, evolution can generate a new enzyme from one that is “close”, that is, shares elements of mechanism or machinery from which the new activity can be built. Nature co-opts old machinery to do new jobs. And sometimes the ability to do the new job is already there, at least at a low level. The biological world is replete with proteins whose capabilities extend well beyond what may be used at any given time. Thus new enzymes are built from promiscuous or side activities that become advantageous in a new biological context, such as when a new food source becomes available.3 Thus a conservative process of accumulating beneficial mutations can innovate because the innovation is already there! The magnificent diversity of the biological world provides the fuel for further innovations. For directed evolution to be a reliable approach to creating new enzymes, we the breeders of proteins must first identify potential catalytic novelty in the form of starting proteins which have at least low levels of a new activity. We therefore look for activities that are known to synthetic chemistry, but perhaps not explored in nature. Cytochrome P450s, whose native functions include a variety of extremely challenging transformations such as hydroxylation, epoxidation, heteroatom oxidations, nitration and more, looked to me like a promising place to start hunting for new activities. Nature had already exploited this evolvable heme-protein assembly and the various reactive intermediates in the catalytic cycle to create all the natural P450 functions. We quickly discovered that many more new, non-natural functions were possible. In the last few years we have engineered P450s and other heme proteins to carry out a plethora of reactions known to synthetic chemists, but not found in biology.4 For example, olefin cyclopropanation by carbene transfer is a reaction well known in the area of transition-metal catalysis, but not known to be catalyzed by an enzyme. In 2012, inspired by much older reports of heme mimics performing such reactions in organic solvents, we discovered that heme proteins catalyze cyclopropanation when provided with diazo carbene precursors and a suitable olefin, in water.5 This promiscuous activity is manifested when the protein encounters the diazo reagent, forms the reactive carbene, and then transfers it to the olefin. Our lab took advantage of this inherent ability of a bacterial cytochrome P450 to evolve a highly efficient enzyme for production of the chiral cis-cyclopropane precursor to the antidepressant medication levomilnacipran.6 Our group and that of Rudi Fasan have since pushed a variety of heme proteins to synthesize other chiral cyclopropane pharmaceutical precursors, including one used in the synthesis of ticagrelor, a medication used to prevent the reoccurrence of heart attacks.7 In our case, we identified a truncated globin from Bacillus subtilis, which catalyzes the reaction at low levels and also showed some selectivity for producing the single, desired diastereomer of the ticagrelor cyclopropane precursor from ethyl diazoacetate and 3,4-difluorostyrene (Figure 1). Just a few generations of directed evolution improved the activity and selectivity of the enzyme so that, of the four possible stereoisomers, it produces the ticagrelor cyclopropane almost exclusively. Because the reaction proceeds in whole Escherichia coli cells which express the evolved enzyme, producing the catalyst is as simple as growing bacteria. A B. subtilis globin variant, engineered by directed evolution, catalyzes the cyclopropanation of 3,4-difluorostyrene to make the desired stereoisomer of a ticagrelor precursor with high selectivity and yield.7a While we were investigating carbene-transfer reactions catalyzed by heme proteins, we also looked into the possibility of evolving enzymes for nitrene-transfer reactions. Inspired by a hint in the literature from the 1980′s to attempt intramolecular C−H amination, we were delighted to find that a cytochrome “P411” exhibited a low level of promiscuous activity with an aryl sulfonyl azide nitrene precursor, and that activity could be improved by directed evolution.8 We purposefully engineered the P411 by replacing the completely conserved cytochrome P450 cysteine ligand, which is bound to the iron center, with serine, a ligand not found in any known natural heme protein. This change shifts the characteristic peak in the CO difference spectrum from λ=450 to 411 nm and abolishes the native monooxygenase activity. It also greatly promotes carbene-transfer and nitrene-transfer activities. After demonstrating that the P411 derived from Bacillus megaterium cytochrome P450 could be engineered for intramolecular C−H amination, and intermolecular aziridination and sulfimidation activities unknown in biological systems, our efforts culminated in cytochrome P411CHA, which catalyzes intermolecular benzylic C−H amination.9 Efficient and highly enantioselective intermolecular amination of C(sp3)−H bonds has long been a challenge in chemical catalysis. Despite screening many different heme proteins and protein variants, however, we never found one with the desired activity until postdoctoral fellow Chris Prier discovered that the P411 variant “P4”, evolved for an intermolecular sulfimidation and rearrangement reaction, had acquired promiscuous activity for benzylic C−H amination. Chris Prier and doctoral student Kelly Zhang then directed the evolution of P4 to create P411CHA, which exhibits hundreds of turnovers for the amination of benzylic C−H bonds with excellent enantioselectivities (>99 % ee).9 Free heme does not catalyze any of these nitrene-transfer reactions, and small-molecule catalysts for direct C−H amination rely heavily on precious metals which are not sustainable. The protein, however, can impart this new reactivity to earth-abundant iron in its porphyrin cofactor, and it is evolvable. Evolution enabled P411CHA to promote nitrenoid formation and transfer to a second substrate over the competing nitrene reduction heavily favored in the parent enzyme,9 a property that would be extremely challenging, if not impossible, to design. In fact, we think of these proteins as chiral, self-assembling, DNA-encoded macromolecular transition-metal complexes whose steric and electronic properties are readily tuned by directed evolution to achieve desired activities and selectivities. Recently we have been exploring enzymes that open yet more chemical space for biocatalysis, including enzymes that form chemical bonds unknown in biology. In the last year we described heme enzymes that catalyze carbene insertion into Si−H and B−H bonds, thus giving living systems their first carbon–silicon10 and carbon–boron11 bond-forming activities. C−Si bonds are useful in medicinal chemistry, imaging agents, elastomers, and a wide variety of consumer products, but they have never been found in biological systems. Until now, the only methods to create these bonds enantioselectively involved multistep syntheses just to prepare chiral reagents or chiral transition-metal complexes. The resulting catalysts are often only poorly active, and an iron-based catalyst had never been reported for this carbene-insertion reaction. Upon screening a collection of heme proteins, postdoctoral fellow Jennifer Kan and her team discovered that a small (124 aa), highly stable cytochrome c from Rhodothermus marinus (Rma cyt c) could catalyze the reaction between ethyl 2-diazopropanoate and phenyldimethylsilane to form the chiral organosilicon product with high enantioselectivity (Figure 2 A). Directed evolution discovered mutations that the enzyme to form C−Si bonds with to turnovers on cyt c and enantioselectivities with greater than % for a wide range of student used the engineered enzyme to make organosilicon products, most of which were as The evolved enzyme also highly for Si−H insertion using substrates other reactive functional 2 formation catalyzed by a variant of Rhodothermus marinus cytochrome The that were to this activity include the ligand The enzyme catalyzes formation of different products with high from and diazo We also an enzyme could catalyze carbene insertion into B−H bonds are known in the biological and the few natural products that include in different forms are to from the Jennifer Kan and that B−H insertion could be thus giving living cells the ability to make chiral products from carbene precursors and with the cytochrome they evolved a efficient evolved cyt c provided to chiral which had never been made from complexes and various carbene for the catalyst to turnovers on cytochrome c a and % (Figure These catalyst turnovers are more than greater than those for known chiral catalysts for the of the could be to make product and functional for these new enzymes open a new world of and chemistry in living systems. of chiral by coli Rhodothermus marinus cytochrome The bacterial catalyst uses complexes and diazo reagents to and in cells by carbene B−H The can be readily on and the of was to give of the products. It has been to that at least some of nature's of proteins can be evolved in the often with only a few mutations, to catalyze reactions amination, and The new enzymes can even create chemical bonds not known in biology These new were made possible by use of reagents not found and nitrene the promiscuous of proteins in the of these synthetic directed evolution to enhance and the new and chemical and to identify the right conditions and reactions to with the right enzymes. The next challenge is to create enzymes for reactions that biology synthetic chemistry has macromolecular catalysts, for example, enzymes can and promote reactions through pathways that would be if not impossible, to with small-molecule catalysts because of with reaction In a powerful of how an enzyme active site can be engineered to promote one reaction over postdoctoral fellow directed the evolution of an which catalyzes the of into the by a that the cytochrome P450 from made some as a side product when it to the looked more and discovered that this promiscuous reactivity not by to the as had been that it instead through a stepwise mechanism intermediates and a (Figure then exploited this side activity to direct the evolution of by far the most active, and the first direct earth-abundant and a the P450 enzyme catalyzes of turnovers for of different including substrates such as and A cytochrome P450 reaction pathways for transfer to The is favored over the stepwise of transfer by an of directed evolution mutations, many of which are from the active can be with for various challenging reactions. the enzyme with and chiral by the enantioselectivity of the It is difficult to how this could be of a macromolecular active The mutations that this reactivity and over substrate the are all over the protein (Figure on the and mechanism that to this remarkable activity are difficult to much less Synthetic catalysts for have not been able to the mechanism because of from the highly favored Instead, synthetic use that require precious metals such as activities with the enzyme. enantioselective method to convert into their chiral was known this enzyme was To enhance for production of can be with other catalysts, such as an to of This enzyme chiral with high and has the of the The is an in the production of many which are now in through the of an evolved with other enzymes or chemical catalysts (Figure that such a direct catalyst is possible may of even better enzymes or even of I have focused this on the efforts of group to heme proteins and to use them to that directed evolution (and a can readily create new enzyme catalysts for reactions first by synthetic chemists and even for reactions which have synthetic The active sites of the new enzymes can high activities and and as well as product which are difficult or to achieve with small-molecule catalysts. enzymes can and direct the of highly reactive intermediates to promote reactions that are the of the enzyme. We that these will be by into the mechanisms of the new reactions from and excellent of directed evolution for non-natural chemistry have been by other including enzymes and enzymes with artificial some of which are described in our The enzymes yet have the of nature's products, and struggles with the metals and other that so much when that directed evolution will be there to draw out the new capabilities and the just as it can do with the promiscuous activities of natural the of evolution realized for we now have a whole new way to look at the products of natural evolution. of simply what enzymes do in we can now the they It will out that they can do a more than we when we use evolution to their is is that evolution is an innovation and nature's products are to be to on new under the of the of A of new enzymes is just to be discovered and used for chemistry that we could only have of just a few years I Jennifer Chris Prier and Zhang for the and hard work that into the I for excellent This work was by the of and the and the innovation The no of is the of and at the of where her on enzyme engineering by directed evolution, with in sustainable and uses innovation mechanisms to new chemical reactions to biology. include the has been to the of and