Deep Confident Steps to New Pockets: Strategies for Docking Generalization

Accurate blind docking has the potential to lead to new biological breakthroughs, but for this promise to be realized, docking methods must generalize well across the proteome. Existing benchmarks, however, fail to rigorously assess generalizability. Therefore, we develop DOCKGEN, a new benchmark based on the ligand binding domains of proteins, and we show that existing machine learning-based docking models have very weak generalization abilities. We carefully analyze the scaling laws of ML-based docking and show that, by scaling data and model size, as well as integrating synthetic data strategies, we are able to significantly increase the generalization capacity and set new state-of-the-art performance across benchmarks. Further, we propose CONFIDENCE BOOTSTRAPPING, a new training paradigm that solely relies on the interaction between diffusion and confidence models and exploits the multi-resolution generation process of diffusion models. We demonstrate that CONFIDENCE BOOTSTRAPPING significantly improves the ability of ML-based docking methods to dock to unseen protein classes, edging closer to accurate and generalizable blind docking methods.

Contributors Gabriele Corso, Arthur Deng, Benjamin Fry, Nicholas Polizzi Learn more

Machine learning for antimicrobial peptide identification and design

Artificial intelligence (AI) and machine learning (ML) models are being deployed in many domains of society and have recently reached the field of drug discovery. Given the increasing prevalence of antimicrobial resistance, as well as the challenges intrinsic to antibiotic development, there is an urgent need to accelerate the design of new antimicrobial therapies. Antimicrobial peptides (AMPs) are therapeutic agents for treating bacterial infections, but their translation into the clinic has been slow owing to toxicity, poor stability, limited cellular penetration and high cost, among other issues. Recent advances in AI and ML have led to breakthroughs in our abilities to predict biomolecular properties and structures and to generate new molecules. The ML-based modelling of peptides may overcome some of the disadvantages associated with traditional drug discovery and aid the rapid development and translation of AMPs. Here, we provide an introduction to this emerging field and survey ML approaches that can be used to address issues currently hindering AMP development. We also outline important limitations that can be addressed for the broader adoption of AMPs in clinical practice, as well as new opportunities in data-driven peptide design.

Contributors: Fangping Wan, Felix Wong, Cesar de la Fuente-Nunez Learn more

Dirichlet Flow Matching with Applications to DNA Sequence Design

Discrete diffusion or flow models could enable faster and more controllable sequence generation than autoregressive models. We show that naïve linear flow matching on the simplex is insufficient toward this goal since it suffers from discontinuities in the training target and further pathologies. To overcome this, we develop Dirichlet flow matching on the simplex based on mixtures of Dirichlet distributions as probability paths. In this framework, we derive a connection between the mixtures' scores and the flow's vector field that allows for classifier and classifier-free guidance. Further, we provide distilled Dirichlet flow matching, which enables one-step sequence generation with minimal performance hits, resulting in O(L) speedups compared to autoregressive models. On complex DNA sequence generation tasks, we demonstrate superior performance compared to all baselines in distributional metrics and in achieving desired design targets for generated sequences. Finally, we show that our classifier-free guidance approach improves unconditional generation and is effective for generating DNA that satisfies design targets. Code is available here: https://github.com/HannesStark/dirichlet-flow-matching

Contributors: Hannes Stark, Bowen Jing, Chenyu Wang, Gabriele Corso, Bonnie Berger Learn more

AlphaFold Meets Flow Matching for Generating Protein Ensembles

The biological functions of proteins often depend on dynamic structural ensembles. In this work, we develop a flow-based generative modeling approach for learning and sampling the conformational landscapes of proteins. We repurpose highly accurate single-state predictors such as AlphaFold and ESMFold and fine-tune them under a custom flow matching framework to obtain sequence-conditoned generative models of protein structure called AlphaFlow and ESMFlow. When trained and evaluated on the PDB, our method provides a superior combination of precision and diversity compared to AlphaFold with MSA subsampling. When further trained on ensembles from all-atom MD, our method accurately captures conformational flexibility, positional distributions, and higher-order ensemble observables for unseen proteins. Moreover, our method can diversify a static PDB structure with faster wall-clock convergence to certain equilibrium properties than replicate MD trajectories, demonstrating its potential as a proxy for expensive physics-based simulations. Code is available here: https://github.com/bjing2016/alphaflow

Contributors: Bowen Jing, Bonnie Berger Learn more

Discovery of a structural class of antibiotics with explainable deep learning

The discovery of novel structural classes of antibiotics is urgently needed to address the ongoing antibiotic resistance crisis. Deep learning approaches have aided in exploring chemical spaces; these typically use black box models and do not provide chemical insights. Here we reasoned that the chemical substructures associated with antibiotic activity learned by neural network models can be identified and used to predict structural classes of antibiotics. We tested this hypothesis by developing an explainable, substructure-based approach for the efficient, deep learning-guided exploration of chemical spaces. We determined the antibiotic activities and human cell cytotoxicity profiles of 39,312 compounds and applied ensembles of graph neural networks to predict antibiotic activity and cytotoxicity for 12,076,365 compounds. Using explainable graph algorithms, we identified substructure-based rationales for compounds with high predicted antibiotic activity and low predicted cytotoxicity. We empirically tested 283 compounds and found that compounds exhibiting antibiotic activity against Staphylococcus aureus were enriched in putative structural classes arising from rationales. Of these structural classes of compounds, one is selective against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci, evades substantial resistance, and reduces bacterial titres in mouse models of MRSA skin and systemic thigh infection. Our approach enables the deep learning-guided discovery of structural classes of antibiotics and demonstrates that machine learning models in drug discovery can be explainable, providing insights into the chemical substructures that underlie selective antibiotic activity.

Contributors: Felix Wong, Erica J. Zheng, Jacqueline A. Valeri, Nina M. Donghia, Melis N. Anahtar, Satotaka Omori, Alicia Li, Andres Cubillos-Ruiz, Aarti Krishnan, Wengong Jin, Abigail L. Manson, Jens Friedrichs, Ralf Helbig, Behnoush Hajian, Dawid K. Fiejtek, Florence F. Wagner, Holly H. Soutter, Ashlee M. Earl, Jonathan M. Stokes, Lars D. Renner Learn more

Particle Guidance: Non-I.I.D. diverse sampling with diffusion models

In light of the widespread success of generative models, a significant amount of research has gone into speeding up their sampling time. However, generative models are often sampled multiple times to obtain a diverse set incurring a cost that is orthogonal to sampling time. We tackle the question of how to improve diversity and sample efficiency by moving beyond the common assumption of independent samples. We propose particle guidance, an extension of diffusion-based generative sampling where a joint-particle time-evolving potential enforces diversity. We analyze theoretically the joint distribution that particle guidance generates, how to learn a potential that achieves optimal diversity, and the connections with methods in other disciplines. Empirically, we test the framework both in the setting of conditional image generation, where we are able to increase diversity without affecting quality, and molecular conformer generation, where we reduce the state-of-the-art median error by 13% on average.

Contributors: Gabriele Corso, Yilun Xu, Valentin de Bortoli Learn more

Improving influenza A vaccine strain selection through deep evolutionary models

Even though vaccines have the potential to significantly alleviate the disease burden of epidemics such as the seasonal flu, current influenza vaccines offer limited protection. According to the Centers for Disease Control and Prevention (CDC), vaccine effectiveness has hovered below 50% for the past decade. Identifying the optimal strains to use in a vaccine is central to increasing its efficacy. However, this task is challenging due to the antigenic drift that occurs during the flu season. In this paper, we propose to select vaccines based on their escapability score, a metric that quantifies the antigenic similarity of vaccine strains with future dominant strains and demonstrates a strong correlation with clinical vaccine effectiveness. We introduce a deep learning-based approach that predicts both the antigenic properties of vaccine strains and the dominance of future circulating viruses, enabling efficient virtual screening of a large number of vaccine compositions. We utilized historical antigenic analysis data from the World Health Organization (WHO) to demonstrate that our model selects vaccine strains that reliably improve over the recommended ones.

Contributors: Wenxian Shi, Rachel Menghua Wu Learn more

Annotating metabolite mass spectra with domain-inspired chemical formula transformers

Metabolomics studies have identified small molecules that mediate cell signaling, competition and disease pathology, in part due to large-scale community efforts to measure tandem mass spectra for thousands of metabolite standards. Nevertheless, the majority of spectra observed in clinical samples cannot be unambiguously matched to known structures. Deep learning approaches to small-molecule structure elucidation have surprisingly failed to rival classical statistical methods, which we hypothesize is due to the lack of in-domain knowledge incorporated into current neural network architectures. Here we introduce a neural network-driven workflow for untargeted metabolomics, Metabolite Inference with Spectrum Transformers (MIST), to annotate tandem mass spectra peaks with chemical structures. Unlike existing approaches, MIST incorporates domain insights into its architecture by encoding peaks with their chemical formula representations, implicitly featurizing pairwise neutral losses and training the network to additionally predict substructure fragments. MIST performs favorably compared with both standard neural architectures and the state-of-the-art kernel method on the task of fingerprint prediction for over 70% of metabolite standards and retrieves 66% of metabolites with equal or improved accuracy, with 29% strictly better. We further demonstrate the utility of MIST by suggesting potential dipeptide and alkaloid structures for differentially abundant spectra found in an inflammatory bowel disease patient cohort.

Contributors: Samuel Goldman, Jeremy Wohlwend, Martin Stražar, Guy Haroush, Ramnik J. Xavier Learn more

Artificial intelligence for science in quantum, atomistic, and continuum systems

Advances in artificial intelligence (AI) are fueling a new paradigm of discoveries in natural sciences. Today, AI has started to advance natural sciences by improving, accelerating, and enabling our understanding of natural phenomena at a wide range of spatial and temporal scales, giving rise to a new area of research known as AI for science (AI4Science). Being an emerging research paradigm, AI4Science is unique in that it is an enormous and highly interdisciplinary area. Thus, a unified and technical treatment of this field is needed yet challenging. This paper aims to provide a technically thorough account of a subarea of AI4Science; namely, AI for quantum, atomistic, and continuum systems. These areas aim at understanding the physical world from the subatomic (wavefunctions and electron density), atomic (molecules, proteins, materials, and interactions), to macro (fluids, climate, and subsurface) scales and form an important subarea of AI4Science. A unique advantage of focusing on these areas is that they largely share a common set of challenges, thereby allowing a unified and foundational treatment. A key common challenge is how to capture physics first principles, especially symmetries, in natural systems by deep learning methods. We provide an in-depth yet intuitive account of techniques to achieve equivariance to symmetry transformations. We also discuss other common technical challenges, including explainability, out-of-distribution generalization, knowledge transfer with foundation and large language models, and uncertainty quantification. To facilitate learning and education, we provide categorized lists of resources that we found to be useful. We strive to be thorough and unified and hope this initial effort may trigger more community interests and efforts to further advance AI4Science. Learn more

De novo design of protein structure and function with RFdiffusion

There has been considerable recent progress in designing new proteins using deep-learning methods. Despite this progress, a general deep-learning framework for protein design that enables solution of a wide range of design challenges, including de novo binder design and design of higher-order symmetric architectures, has yet to be described. Diffusion models have had considerable success in image and language generative modelling but limited success when applied to protein modelling, probably due to the complexity of protein backbone geometry and sequence–structure relationships. Here we show that by fine-tuning the RoseTTAFold structure prediction network on protein structure denoising tasks, we obtain a generative model of protein backbones that achieves outstanding performance on unconditional and topology-constrained protein monomer design, protein binder design, symmetric oligomer design, enzyme active site scaffolding and symmetric motif scaffolding for therapeutic and metal-binding protein design. We demonstrate the power and generality of the method, called RoseTTAFold diffusion (RFdiffusion), by experimentally characterizing the structures and functions of hundreds of designed symmetric assemblies, metal-binding proteins and protein binders. The accuracy of RFdiffusion is confirmed by the cryogenic electron microscopy structure of a designed binder in complex with influenza haemagglutinin that is nearly identical to the design model. In a manner analogous to networks that produce images from user-specified inputs, RFdiffusion enables the design of diverse functional proteins from simple molecular specifications.

Contributors: Joseph L. Watson, David Juergens, Nathaniel R. Bennett, Brian L. Trippe, Helen E. Eisenach, Woody Ahern, Andrew J. Borst, Robert J. Ragotte, Lukas F. Milles, Basile I. M. Wicky, Nikita Hanikel, Samuel J. Pellock, Alexis Courbet, William Sheffler, Jue Wang, Preetham Venkatesh, Isaac Sappington, Susana Vázquez Torres, Anna Lauko, Valentin De Bortoli, Emile Mathieu, Sergey Ovchinnikov, Frank DiMaio, Minkyung Baek & David Baker Learn more
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