Conditional Normalizing Flows for Active Learning of Coarse-Grained Molecular Representations

Efficient sampling of the Boltzmann distribution of molecular systems is a long-standing challenge. Recently, instead of generating long molecular dynamics simulations, generative machine learning methods such as normalizing flows have been used to learn the Boltzmann distribution directly, without samples. However, this approach is susceptible to mode collapse and thus often does not explore the full configurational space. In this work, we address this challenge by separating the problem into two levels, the fine-grained and coarse-grained degrees of freedom. A normalizing flow conditioned on the coarse-grained space yields a probabilistic connection between the two levels. To explore the configurational space, we employ coarse-grained simulations with active learning which allows us to update the flow and make all-atom potential energy evaluations only when necessary. Using alanine dipeptide as an example, we show that our methods obtain a speedup to molecular dynamics simulations of approximately 15.9 to 216.2 compared to the speedup of 4.5 of the current state-of-the-art machine learning approach.

Contextualized Policy Recovery: Modeling and Interpreting Medical Decisions with Adaptive Imitation Learning

Interpretable policy learning seeks to estimate intelligible decision policies from observed actions; however, existing models fall short by forcing a tradeoff between accuracy and interpretability. This tradeoff limits data-driven interpretations of human decision-making process. e.g. to audit medical decisions for biases and suboptimal practices, we require models of decision processes which provide concise descriptions of complex behaviors. Fundamentally, existing approaches are burdened by this tradeoff because they represent the underlying decision process as a universal policy, when in fact human decisions are dynamic and can change drastically with contextual information. Thus, we propose Contextualized Policy Recovery (CPR), which re-frames the problem of modeling complex decision processes as a multi-task learning problem in which complex decision policies are comprised of context-specific policies. CPR models each context-specific policy as a linear observation-to-action mapping, and generates new decision models $\textit{on-demand}$ as contexts are updated with new observations. CPR is compatible with fully offline and partially observable decision environments, and can be tailored to incorporate any recurrent black-box model or interpretable decision model. We assess CPR through studies on simulated and real data, achieving state-of-the-art performance on the canonical tasks of predicting antibiotic prescription in intensive care units ($+22\%$ AUROC vs. previous SOTA) and predicting MRI prescription for Alzheimer's patients ($+7.7\%$ AUROC vs. previous SOTA). With this improvement in predictive performance, CPR closes the accuracy gap between interpretable and black-box methods for policy learning, allowing high-resolution exploration and analysis of context-specific decision models.

Mitigating Molecular Aggregation in Drug Discovery with Predictive Insights from Explainable AI

As the importance of high-throughput screening (HTS) continues to grow due to its value in early stage drug discovery and data generation for training machine learning models, there is a growing need for robust methods for pre-screening compounds to identify and prevent false-positive hits. Small, colloidally aggregating molecules are one of the primary sources of false-positive hits in high-throughput screens, making them an ideal candidate to target for removal from libraries using predictive pre-screening tools. However, a lack of understanding of the causes of molecular aggregation introduces difficulty in the development of predictive tools for detecting aggregating molecules. Herein, we present an examination of the molecular features differentiating datasets of aggregating and non-aggregating molecules, as well as a machine learning approach to predicting molecular aggregation. Our method uses explainable graph neural networks and counterfactuals to reliably predict and explain aggregation, giving additional insights and design rules for future screening. The integration of this method in HTS approaches will help combat false positives, providing better lead molecules more rapidly and thus accelerating drug discovery cycles.

Quantifying the Intrinsic Usefulness of Attributional Explanations for Graph Neural Networks with Artificial Simulatability Studies

Despite the increasing relevance of explainable AI, assessing the quality of explanations remains a challenging issue. Due to the high costs associated with human-subject experiments, various proxy metrics are often used to approximately quantify explanation quality. Generally, one possible interpretation of the quality of an explanation is its inherent value for teaching a related concept to a student. In this work, we extend artificial simulatability studies to the domain of graph neural networks. Instead of costly human trials, we use explanation-supervisable graph neural networks to perform simulatability studies to quantify the inherent usefulness of attributional graph explanations. We perform an extensive ablation study to investigate the conditions under which the proposed analyses are most meaningful. We additionally validate our methods applicability on real-world graph classification and regression datasets. We find that relevant explanations can significantly boost the sample efficiency of graph neural networks and analyze the robustness towards noise and bias in the explanations. We believe that the notion of usefulness obtained from our proposed simulatability analysis provides a dimension of explanation quality that is largely orthogonal to the common practice of faithfulness and has great potential to expand the toolbox of explanation quality assessments, specifically for graph explanations.

Neural networks trained on synthetically generated crystals can extract structural information from ICSD powder X-ray diffractograms

Machine learning techniques have successfully been used to extract structural information such as the crystal space group from powder X-ray diffractograms. However, training directly on simulated diffractograms from databases such as the ICSD is challenging due to its limited size, class-inhomogeneity, and bias toward certain structure types. We propose an alternative approach of generating synthetic crystals with random coordinates by using the symmetry operations of each space group. Based on this approach, we demonstrate online training of deep ResNet-like models on up to a few million unique on-the-fly generated synthetic diffractograms per hour. For our chosen task of space group classification, we achieved a test accuracy of 79.9% on unseen ICSD structure types from most space groups. This surpasses the 56.1% accuracy of the current state-of-the-art approach of training on ICSD crystals directly. Our results demonstrate that synthetically generated crystals can be used to extract structural information from ICSD powder diffractograms, which makes it possible to apply very large state-of-the-art machine learning models in the area of powder X-ray diffraction. We further show first steps toward applying our methodology to experimental data, where automated XRD data analysis is crucial, especially in high-throughput settings. While we focused on the prediction of the space group, our approach has the potential to be extended to related tasks in the future.

Connectivity Optimized Nested Graph Networks for Crystal Structures

Graph neural networks (GNNs) have been applied to a large variety of applications in materials science and chemistry. Here, we recapitulate the graph construction for crystalline (periodic) materials and investigate its impact on the GNNs model performance. We suggest the asymmetric unit cell as a representation to reduce the number of atoms by using all symmetries of the system. With a simple but systematically built GNN architecture based on message passing and line graph templates, we furthermore introduce a general architecture (Nested Graph Network, NGN) that is applicable to a wide range of tasks and systematically improves state-of-the-art results on the MatBench benchmark datasets.

Actively Learning Costly Reward Functions for Reinforcement Learning

Transfer of recent advances in deep reinforcement learning to real-world applications is hindered by high data demands and thus low efficiency and scalability. Through independent improvements of components such as replay buffers or more stable learning algorithms, and through massively distributed systems, training time could be reduced from several days to several hours for standard benchmark tasks. However, while rewards in simulated environments are well-defined and easy to compute, reward evaluation becomes the bottleneck in many real-world environments, e.g., in molecular optimization tasks, where computationally demanding simulations or even experiments are required to evaluate states and to quantify rewards. Therefore, training might become prohibitively expensive without an extensive amount of computational resources and time. We propose to alleviate this problem by replacing costly ground-truth rewards with rewards modeled by neural networks, counteracting non-stationarity of state and reward distributions during training with an active learning component. We demonstrate that using our proposed ACRL method (Actively learning Costly rewards for Reinforcement Learning), it is possible to train agents in complex real-world environments orders of magnitudes faster. By enabling the application of reinforcement learning methods to new domains, we show that we can find interesting and non-trivial solutions to real-world optimization problems in chemistry, materials science and engineering.

MEGAN: Multi-Explanation Graph Attention Network

Explainable artificial intelligence (XAI) methods are expected to improve trust during human-AI interactions, provide tools for model analysis and extend human understanding of complex problems. Explanation-supervised training allows to improve explanation quality by training self-explaining XAI models on ground truth or human-generated explanations. However, existing explanation methods have limited expressiveness and interoperability due to the fact that only single explanations in form of node and edge importance are generated. To that end we propose the novel multi-explanation graph attention network (MEGAN). Our fully differentiable, attention-based model features multiple explanation channels, which can be chosen independently of the task specifications. We first validate our model on a synthetic graph regression dataset. We show that for the special single explanation case, our model significantly outperforms existing post-hoc and explanation-supervised baseline methods. Furthermore, we demonstrate significant advantages when using two explanations, both in quantitative explanation measures as well as in human interpretability. Finally, we demonstrate our model's capabilities on multiple real-world datasets. We find that our model produces sparse high-fidelity explanations consistent with human intuition about those tasks and at the same time matches state-of-the-art graph neural networks in predictive performance, indicating that explanations and accuracy are not necessarily a trade-off.

On scientific understanding with artificial intelligence

Imagine an oracle that correctly predicts the outcome of every particle physics experiment, the products of every chemical reaction, or the function of every protein. Such an oracle would revolutionize science and technology as we know them. However, as scientists, we would not be satisfied with the oracle itself. We want more. We want to comprehend how the oracle conceived these predictions. This feat, denoted as scientific understanding, has frequently been recognized as the essential aim of science. Now, the ever-growing power of computers and artificial intelligence poses one ultimate question: How can advanced artificial systems contribute to scientific understanding or achieve it autonomously? We are convinced that this is not a mere technical question but lies at the core of science. Therefore, here we set out to answer where we are and where we can go from here. We first seek advice from the philosophy of science to understand scientific understanding. Then we review the current state of the art, both from literature and by collecting dozens of anecdotes from scientists about how they acquired new conceptual understanding with the help of computers. Those combined insights help us to define three dimensions of android-assisted scientific understanding: The android as a I) computational microscope, II) resource of inspiration and the ultimate, not yet existent III) agent of understanding. For each dimension, we explain new avenues to push beyond the status quo and unleash the full power of artificial intelligence's contribution to the central aim of science. We hope our perspective inspires and focuses research towards androids that get new scientific understanding and ultimately bring us closer to true artificial scientists.

SELFIES and the future of molecular string representations

Artificial intelligence (AI) and machine learning (ML) are expanding in popularity for broad applications to challenging tasks in chemistry and materials science. Examples include the prediction of properties, the discovery of new reaction pathways, or the design of new molecules. The machine needs to read and write fluently in a chemical language for each of these tasks. Strings are a common tool to represent molecular graphs, and the most popular molecular string representation, SMILES, has powered cheminformatics since the late 1980s. However, in the context of AI and ML in chemistry, SMILES has several shortcomings -- most pertinently, most combinations of symbols lead to invalid results with no valid chemical interpretation. To overcome this issue, a new language for molecules was introduced in 2020 that guarantees 100\% robustness: SELFIES (SELF-referencIng Embedded Strings). SELFIES has since simplified and enabled numerous new applications in chemistry. In this manuscript, we look to the future and discuss molecular string representations, along with their respective opportunities and challenges. We propose 16 concrete Future Projects for robust molecular representations. These involve the extension toward new chemical domains, exciting questions at the interface of AI and robust languages and interpretability for both humans and machines. We hope that these proposals will inspire several follow-up works exploiting the full potential of molecular string representations for the future of AI in chemistry and materials science.