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The discovery of new materials can bring enormous societal and technological progress. In this context, exploring completely the large space of potential materials is computationally intractable. Here, we review methods for achieving inverse design, which aims to discover tailored materials from the starting point of a particular desired functionality. Recent advances from the rapidly growing field of artificial intelligence, mostly from the subfield of machine learning, have resulted in a fertile exchange of ideas, where approaches to inverse molecular design are being proposed and employed at a rapid pace. Among these, deep generative models have been applied to numerous classes of materials: rational design of prospective drugs, synthetic routes to organic compounds, and optimization of photovoltaics and redox flow batteries, as well as a variety of other solid-state materials.

Generative models are becoming a tool of choice for exploring the molecular space. These models learn on a large training dataset and produce novel molecular structures with similar properties. Generated structures can be utilized for virtual screening or training semi-supervized predictive models in the downstream tasks. While there are plenty of generative models, it is unclear how to compare and rank them. In this work, we introduce a benchmarking platform called Molecular Sets (MOSES) to standardize training and comparison of molecular generative models. MOSES provides training and testing datasets, and a set of metrics to evaluate the quality and diversity of generated structures. We have implemented and compared several molecular generation models and suggest to use our results as reference points for further advancements in generative chemistry research. The platform and source code are available at https://github.com/molecularsets/moses .

Hearing and vision sensory systems are tuned to the natural statistics of acoustic and electromagnetic energy on earth and are evolved to be sensitive in ethologically relevant ranges. But what are the natural statistics of odors , and how do olfactory systems exploit them? Dissecting an accurate machine learning model (Lee et al., 2022) for human odor perception, we find a computable representation for odor at the molecular level that can predict the odor-evoked receptor, neural, and behavioral responses of nearly all terrestrial organisms studied in olfactory neuroscience. Using this olfactory representation (principal odor map [POM]), we find that odorous compounds with similar POM representations are more likely to co-occur within a substance and be metabolically closely related; metabolic reaction sequences (Caspi et al., 2014) also follow smooth paths in POM despite large jumps in molecular structure. Just as the brain’s visual representations have evolved around the natural statistics of light and shapes, the natural statistics of metabolism appear to shape the brain’s representation of the olfactory world.

Redox biochemistry plays a key role in the transduction of chemical energy in living systems. However, the compounds observed in metabolic redox reactions are a minuscule fraction of chemical space. It is not clear whether compounds that ended up being selected as metabolites display specific properties that distinguish them from nonbiological compounds. Here, we introduce a systematic approach for comparing the chemical space of all possible redox states of linear-chain carbon molecules to the corresponding metabolites that appear in biology. Using cheminformatics and quantum chemistry, we analyze the physicochemical and thermodynamic properties of the biological and nonbiological compounds. We find that, among all compounds, aldose sugars have the highest possible number of redox connections to other molecules. Metabolites are enriched in carboxylic acid functional groups and depleted of ketones and aldehydes and have higher solubility than nonbiological compounds. Upon constructing the energy landscape for the full chemical space as a function of pH and electron-donor potential, we find that metabolites tend to have lower Gibbs energies than nonbiological molecules. Finally, we generate Pourbaix phase diagrams that serve as a thermodynamic atlas to indicate which compounds are energy minima in redox chemical space across a set of pH values and electrondonor potentials. While escape from thermodynamic equilibrium toward kinetically driven states is a hallmark of life and its origin, we envision that a deeper quantitative understanding of the environment-dependent thermodynamic landscape of putative prebiotic molecules will provide a crucial reference for future origins-of-life models.

Thermodynamics dictates the structure and function of metabolism. Redox reactions drive cellular energy and material flow. Hence, accurately quantifying the thermodynamics of redox reactions should reveal design principles that shape cellular metabolism. However, only few redox potentials have been measured, and mostly with inconsistent experimental setups. Here, we develop a quantum chemistry approach to calculate redox potentials of biochemical reactions and demonstrate our method predicts experimentally measured potentials with unparalleled accuracy. We then calculate the potentials of all redox pairs that can be generated from biochemically relevant compounds and highlight fundamental trends in redox biochemistry. We further address the question of why NAD/NADP are used as primary electron carriers, demonstrating how their physiological potential range fits the reactions of central metabolism and minimizes the concentration of reactive carbonyls. The use of quantum chemistry can revolutionize our understanding of biochemical phenomena by enabling fast and accurate calculation of thermodynamic values.

Olfaction—how molecules are perceived as odors to humans—is a relatively less understood sensory system compared to vision or hearing. Recently, the principal odor map (POM) was introduced to digitize the olfactory properties of single compounds. However, smells in real life are not pure single molecules, but complex mixtures of molecules, whose representations remain relatively under-explored due to limited data in olfactory mixtures. We introduce POMMix , a mixture model extension of POM which leverages mono-molecular olfactory data to build meaningful mixture representations of smells. Our model builds upon the symmetries of the problem space in a hierarchical manner: (1) graph neural networks for building mono-molecular embeddings, (2) attention mechanisms for aggregating molecular representations into mixture representations, and (3) cosine prediction heads to encode olfactory perceptual distance in the mixture embedding space. POMMix achieves state-of-the-art performance across multiple datasets. We perform comprehensive ablation studies of the components of POMMix to understand the contribution of each component. We evaluate the generalizability of the model, explore olfactory phenomena with the representations, and analyze the interpretability of the representations. Our work advances the effort to digitize olfaction, highlighting the synergy of domain expertise and deep learning in crafting mixture representations in low-data regimes.

Reticular frameworks are crystalline porous materials that form via the self-assembly of molecular building blocks in different topologies, with many having desirable properties for gas storage, separation, catalysis, biomedical applications and so on. The notable variety of building blocks makes reticular chemistry both promising and challenging for prospective materials design. Here we propose an automated nanoporous materials discovery platform powered by a supramolecular variational autoencoder for the generative design of reticular materials. We demonstrate the automated design process with a class of metal–organic framework (MOF) structures and the goal of separating carbon dioxide from natural gas or flue gas. Our model shows high fidelity in capturing MOF structural features. We show that the autoencoder has a promising optimization capability when jointly trained with multiple top adsorbent candidates identified for superior gas separation. MOFs discovered here are strongly competitive against some of the best-performing MOFs/zeolites ever reported. Reticular frameworks are crystalline porous materials with desirable properties such as gas separation, but their large design space presents a challenge. An automated nanoporous materials discovery platform powered by a supramolecular variational autoencoder can efficiently explore this space.

Molecular representation is a critical element in our understanding of the physical world and the foundation for modern molecular machine learning. Previous molecular machine learning models have used strings, fingerprints, global features and simple molecular graphs that are inherently information-sparse representations. However, as the complexity of prediction tasks increases, the molecular representation needs to encode higher fidelity information. This work introduces a new approach to infusing quantum-chemical-rich information into molecular graphs via stereoelectronic effects, enhancing expressivity and interpretability. Learning to predict the stereoelectronics-infused representation with a tailored double graph neural network workflow enables its application to any downstream molecular machine learning task without expensive quantum-chemical calculations. We show that the explicit addition of stereoelectronic information substantially improves the performance of message-passing two-dimensional machine learning models for molecular property prediction. We show that the learned representations trained on small molecules can accurately extrapolate to much larger molecular structures, yielding chemical insight into orbital interactions for previously intractable systems, such as entire proteins, opening new avenues of molecular design. Finally, we have developed a web application (simg.cheme.cmu.edu) where users can rapidly explore stereoelectronic information for their own molecular systems. Boiko et al. enhance expressiveness and interpretability of molecular representation in graph neural networks by including quantum-chemical-rich information into molecular graphs.

Thermodynamics plays an increasingly important role in modeling and engineering metabolism. We present the first nonempirical computational method for estimating standard Gibbs reaction energies of metabolic reactions based on quantum chemistry, which can help fill in the gaps in the existing thermodynamic data. When applied to a test set of reactions from core metabolism, the quantum chemical approach is comparable in accuracy to group contribution methods for isomerization and group transfer reactions and for reactions not including multiply charged anions. The errors in standard Gibbs reaction energy estimates are correlated with the charges of the participating molecules. The quantum chemical approach is amenable to systematic improvements and holds potential for providing thermodynamic data for all of metabolism.

Computational tools encompassing integrated molecular prediction, analysis, and generation are key for molecular design in a variety of critical applications. In this work, we develop a workflow for molecular analysis (MOLAN) that integrates an ensemble of supervised and unsupervised machine learning techniques to analyze molecular data sets. The MOLAN workflow combines molecular featurization, clustering algorithms, uncertainty analysis, low-bias dataset construction, high-performance regression models, graph-based molecular embeddings and attribution, and a semi-supervised variational autoencoder based on the novel SELFIES representation to enable molecular design. We demonstrate the utility of the MOLAN workflow in the context of a challenging multi-molecule property prediction problem: the determination of melting points solely from single molecule structure. This application serves as a case study for how to employ the MOLAN workflow in the context of molecular property prediction.