Nathan C. Frey

Nathan C. Frey, Daniel Berenberg, Karina Zadorozhny et al. · berkeley

We resolve difficulties in training and sampling from a discrete generative model by learning a smoothed energy function, sampling from the smoothed data manifold with Langevin Markov chain Monte Carlo (MCMC), and projecting back to the true data manifold with one-step denoising. Our Discrete Walk-Jump Sampling formalism combines the contrastive divergence training of an energy-based model and improved sample quality of a score-based model, while simplifying training and sampling by requiring only a single noise level. We evaluate the robustness of our approach on generative modeling of antibody proteins and introduce the distributional conformity score to benchmark protein generative models. By optimizing and sampling from our models for the proposed distributional conformity score, 97-100% of generated samples are successfully expressed and purified and 70% of functional designs show equal or improved binding affinity compared to known functional antibodies on the first attempt in a single round of laboratory experiments. We also report the first demonstration of long-run fast-mixing MCMC chains where diverse antibody protein classes are visited in a single MCMC chain.

Nataša Tagasovska, Nathan C. Frey, Andreas Loukas et al. · berkeley

Deep generative models have emerged as a popular machine learning-based approach for inverse design problems in the life sciences. However, these problems often require sampling new designs that satisfy multiple properties of interest in addition to learning the data distribution. This multi-objective optimization becomes more challenging when properties are independent or orthogonal to each other. In this work, we propose a Pareto-compositional energy-based model (pcEBM), a framework that uses multiple gradient descent for sampling new designs that adhere to various constraints in optimizing distinct properties. We demonstrate its ability to learn non-convex Pareto fronts and generate sequences that simultaneously satisfy multiple desired properties across a series of real-world antibody design tasks.

Dan Zhao, Nathan C. Frey, Joseph McDonald et al. · berkeley

As research and practice in artificial intelligence (A.I.) grow in leaps and bounds, the resources necessary to sustain and support their operations also grow at an increasing pace. While innovations and applications from A.I. have brought significant advances, from applications to vision and natural language to improvements to fields like medical imaging and materials engineering, their costs should not be neglected. As we embrace a world with ever-increasing amounts of data as well as research and development of A.I. applications, we are sure to face an ever-mounting energy footprint to sustain these computational budgets, data storage needs, and more. But, is this sustainable and, more importantly, what kind of setting is best positioned to nurture such sustainable A.I. in both research and practice? In this paper, we outline our outlook for Green A.I. -- a more sustainable, energy-efficient and energy-aware ecosystem for developing A.I. across the research, computing, and practitioner communities alike -- and the steps required to arrive there. We present a bird's eye view of various areas for potential changes and improvements from the ground floor of AI's operational and hardware optimizations for datacenters/HPCs to the current incentive structures in the world of A.I. research and practice, and more. We hope these points will spur further discussion, and action, on some of these issues and their potential solutions.

Teddy Koker, Keegan Quigley, Will Spaeth et al. · berkeley, mit

Recent work has shown the potential of graph neural networks to efficiently predict material properties, enabling high-throughput screening of materials. Training these models, however, often requires large quantities of labelled data, obtained via costly methods such as ab initio calculations or experimental evaluation. By leveraging a series of material-specific transformations, we introduce CrystalCLR, a framework for constrastive learning of representations with crystal graph neural networks. With the addition of a novel loss function, our framework is able to learn representations competitive with engineered fingerprinting methods. We also demonstrate that via model finetuning, contrastive pretraining can improve the performance of graph neural networks for prediction of material properties and significantly outperform traditional ML models that use engineered fingerprints. Lastly, we observe that CrystalCLR produces material representations that form clusters by compound class.

Michael Maser, Ji Won Park, Joshua Yao-Yu Lin et al. · berkeley

We investigate Siamese networks for learning related embeddings for augmented samples of molecular conformers. We find that a non-contrastive (positive-pair only) auxiliary task aids in supervised training of Euclidean neural networks (E3NNs) and increases manifold smoothness (MS) around point-cloud geometries. We demonstrate this property for multiple drug-activity prediction tasks while maintaining relevant performance metrics, and propose an extension of MS to probabilistic and regression settings. We provide an analysis of representation collapse, finding substantial effects of task-weighting, latent dimension, and regularization. We expect the presented protocol to aid in the development of reliable E3NNs from molecular conformers, even for small-data drug discovery programs.

Nataša Tagasovska, Ji Won Park, Matthieu Kirchmeyer et al.

Machine learning (ML) has demonstrated significant promise in accelerating drug design. Active ML-guided optimization of therapeutic molecules typically relies on a surrogate model predicting the target property of interest. The model predictions are used to determine which designs to evaluate in the lab, and the model is updated on the new measurements to inform the next cycle of decisions. A key challenge is that the experimental feedback from each cycle inspires changes in the candidate proposal or experimental protocol for the next cycle, which lead to distribution shifts. To promote robustness to these shifts, we must account for them explicitly in the model training. We apply domain generalization (DG) methods to classify the stability of interactions between an antibody and antigen across five domains defined by design cycles. Our results suggest that foundational models and ensembling improve predictive performance on out-of-distribution domains. We publicly release our codebase extending the DG benchmark ``DomainBed,'' and the associated dataset of antibody sequences and structures emulating distribution shifts across design cycles.

Aya Abdelsalam Ismail, Tuomas Oikarinen, Amy Wang et al.

We introduce Concept Bottleneck Protein Language Models (CB-pLM), a generative masked language model with a layer where each neuron corresponds to an interpretable concept. Our architecture offers three key benefits: i) Control: We can intervene on concept values to precisely control the properties of generated proteins, achieving a 3 times larger change in desired concept values compared to baselines. ii) Interpretability: A linear mapping between concept values and predicted tokens allows transparent analysis of the model's decision-making process. iii) Debugging: This transparency facilitates easy debugging of trained models. Our models achieve pre-training perplexity and downstream task performance comparable to traditional masked protein language models, demonstrating that interpretability does not compromise performance. While adaptable to any language model, we focus on masked protein language models due to their importance in drug discovery and the ability to validate our model's capabilities through real-world experiments and expert knowledge. We scale our CB-pLM from 24 million to 3 billion parameters, making them the largest Concept Bottleneck Models trained and the first capable of generative language modeling.

Angelica Chen, Samuel D. Stanton, Frances Ding et al.

Although large language models (LLMs) have shown promise in biomolecule optimization problems, they incur heavy computational costs and struggle to satisfy precise constraints. On the other hand, specialized solvers like LaMBO-2 offer efficiency and fine-grained control but require more domain expertise. Comparing these approaches is challenging due to expensive laboratory validation and inadequate synthetic benchmarks. We address this by introducing Ehrlich functions, a synthetic test suite that captures the geometric structure of biophysical sequence optimization problems. With prompting alone, off-the-shelf LLMs struggle to optimize Ehrlich functions. In response, we propose LLOME (Language Model Optimization with Margin Expectation), a bilevel optimization routine for online black-box optimization. When combined with a novel preference learning loss, we find LLOME can not only learn to solve some Ehrlich functions, but can even perform as well as or better than LaMBO-2 on moderately difficult Ehrlich variants. However, LLMs also exhibit some likelihood-reward miscalibration and struggle without explicit rewards. Our results indicate LLMs can occasionally provide significant benefits, but specialized solvers are still competitive and incur less overhead.

Ewan R. S. Wallace, Nathan C. Frey, Joshua A. Rackers

Ligand strain energy, the energy difference between the bound and unbound conformations of a ligand, is an important component of structure-based small molecule drug design. A large majority of observed ligands in protein-small molecule co-crystal structures bind in low-strain conformations, making strain energy a useful filter for structure-based drug design. In this work we present a tool for calculating ligand strain with a high accuracy. StrainRelief uses a MACE Neural Network Potential (NNP), trained on a large database of Density Functional Theory (DFT) calculations to estimate ligand strain of neutral molecules with quantum accuracy. We show that this tool estimates strain energy differences relative to DFT to within 1.4 kcal/mol, more accurately than alternative NNPs. These results highlight the utility of NNPs in drug discovery, and provide a useful tool for drug discovery teams.

Nate Gruver, Samuel Stanton, Nathan C. Frey et al.

A popular approach to protein design is to combine a generative model with a discriminative model for conditional sampling. The generative model samples plausible sequences while the discriminative model guides a search for sequences with high fitness. Given its broad success in conditional sampling, classifier-guided diffusion modeling is a promising foundation for protein design, leading many to develop guided diffusion models for structure with inverse folding to recover sequences. In this work, we propose diffusioN Optimized Sampling (NOS), a guidance method for discrete diffusion models that follows gradients in the hidden states of the denoising network. NOS makes it possible to perform design directly in sequence space, circumventing significant limitations of structure-based methods, including scarce data and challenging inverse design. Moreover, we use NOS to generalize LaMBO, a Bayesian optimization procedure for sequence design that facilitates multiple objectives and edit-based constraints. The resulting method, LaMBO-2, enables discrete diffusions and stronger performance with limited edits through a novel application of saliency maps. We apply LaMBO-2 to a real-world protein design task, optimizing antibodies for higher expression yield and binding affinity to several therapeutic targets under locality and developability constraints, attaining a 99% expression rate and 40% binding rate in exploratory in vitro experiments.

Mario Krenn, Qianxiang Ai, Senja Barthel et al.

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.

Nathan C. Frey, Baolin Li, Joseph McDonald et al.

Deep learning (DL) workflows demand an ever-increasing budget of compute and energy in order to achieve outsized gains. Neural architecture searches, hyperparameter sweeps, and rapid prototyping consume immense resources that can prevent resource-constrained researchers from experimenting with large models and carry considerable environmental impact. As such, it becomes essential to understand how different deep neural networks (DNNs) and training leverage increasing compute and energy resources -- especially specialized computationally-intensive models across different domains and applications. In this paper, we conduct over 3,400 experiments training an array of deep networks representing various domains/tasks -- natural language processing, computer vision, and chemistry -- on up to 424 graphics processing units (GPUs). During training, our experiments systematically vary compute resource characteristics and energy-saving mechanisms such as power utilization and GPU clock rate limits to capture and illustrate the different trade-offs and scaling behaviors each representative model exhibits under various resource and energy-constrained regimes. We fit power law models that describe how training time scales with available compute resources and energy constraints. We anticipate that these findings will help inform and guide high-performance computing providers in optimizing resource utilization, by selectively reducing energy consumption for different deep learning tasks/workflows with minimal impact on training.

Nathan C. Frey, Vijay Gadepally, Bharath Ramsundar

We propose a framework using normalizing-flow based models, SELF-Referencing Embedded Strings, and multi-objective optimization that efficiently generates small molecules. With an initial training set of only 100 small molecules, FastFlows generates thousands of chemically valid molecules in seconds. Because of the efficient sampling, substructure filters can be applied as desired to eliminate compounds with unreasonable moieties. Using easily computable and learned metrics for druglikeness, synthetic accessibility, and synthetic complexity, we perform a multi-objective optimization to demonstrate how FastFlows functions in a high-throughput virtual screening context. Our model is significantly simpler and easier to train than autoregressive molecular generative models, and enables fast generation and identification of druglike, synthesizable molecules.

Nathan C. Frey, Siddharth Samsi, Bharath Ramsundar et al.

Artificial intelligence has not yet revolutionized the design of materials and molecules. In this perspective, we identify four barriers preventing the integration of atomistic deep learning, molecular science, and high-performance computing. We outline focused research efforts to address the opportunities presented by these challenges.

Nathan C. Frey, Siddharth Samsi, Joseph McDonald et al.

Deep learning in molecular and materials sciences is limited by the lack of integration between applied science, artificial intelligence, and high-performance computing. Bottlenecks with respect to the amount of training data, the size and complexity of model architectures, and the scale of the compute infrastructure are all key factors limiting the scaling of deep learning for molecules and materials. Here, we present $\textit{LitMatter}$, a lightweight framework for scaling molecular deep learning methods. We train four graph neural network architectures on over 400 GPUs and investigate the scaling behavior of these methods. Depending on the model architecture, training time speedups up to $60\times$ are seen. Empirical neural scaling relations quantify the model-dependent scaling and enable optimal compute resource allocation and the identification of scalable molecular geometric deep learning model implementations.

Matthew L. Weiss, Nathan C. Frey, Siddharth Samsi et al.

Traditional frequency based projection filters, or projection operators (PO), separate signal and noise through a series of transformations which remove frequencies where noise is present. However, this technique relies on a priori knowledge of what frequencies contain signal and noise and that these frequencies do not overlap, which is difficult to achieve in practice. To address these issues, we introduce a PO-neural network hybrid model, the Pseudo Projection Operator (PPO), which leverages a neural network to perform frequency selection. We compare the filtering capabilities of a PPO, PO, and denoising autoencoder (DAE) on the University of Rochester Multi-Modal Music Performance Dataset with a variety of added noise types. In the majority of experiments, the PPO outperforms both the PO and DAE. Based upon these results, we suggest future application of the PPO to filtering problems in the physical and biological sciences.