arXiv subjects

Bonnie Berger

Publications and source records attributed to Bonnie Berger.

At least 19 recordsLinked to original sources

arXiv2026

SwitchCraft: A Programmatic Framework for Designing State-Switching Proteins

Multistate mechanisms underlie many of the complex functions observed in natural proteins. The ability to rationally design multistate proteins would have transformative implications for many areas of biotechnology, yet lies beyond the capabilities of existing deep learning frameworks for protein design. To address this gap, we introduce SwitchCraft, a versatile and programmatic framework for designing state-switching proteins based on backpropagation through compositional design constraints parameterized by structure prediction models. In silico evaluations demonstrate success on a wide range of state-switching functional primitives, from allosteric regulation of motifs to discrimination of bound ligand identities. Using these primitives, we demonstrate an in silico strategy for de novo design of fluorescent biosensors to arbitrary small molecule analytes. These results position SwitchCraft at the inception of a powerful paradigm for higher-order functional protein design. Code is available at https://github.com/bjing2016/switchcraft.

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arXiv2026

Learning residue level protein dynamics with multiscale Gaussians

Many methods have been developed to predict static protein structures, however understanding the dynamics of protein structure is essential for elucidating biological function. While molecular dynamics (MD) simulations remain the in silico gold standard, its high computational cost limits scalability. We present DynaProt, a lightweight, SE(3)-invariant framework that predicts rich descriptors of protein dynamics directly from static structures. By casting the problem through the lens of multivariate Gaussians, DynaProt estimates dynamics at two complementary scales: (1) per-residue marginal anisotropy as $3 \times 3$ covariance matrices capturing local flexibility, and (2) joint scalar covariances encoding pairwise dynamic coupling across residues. From these dynamics outputs, DynaProt achieves high accuracy in predicting residue-level flexibility (RMSF) and, remarkably, enables reasonable reconstruction of the full covariance matrix for fast ensemble generation. Notably, it does so using orders of magnitude fewer parameters than prior methods. Our results highlight the potential of direct protein dynamics prediction as a scalable alternative to existing methods.

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arXiv2025

E-valuator: Reliable Agent Verifiers with Sequential Hypothesis Testing

Agentic AI systems execute a sequence of actions, such as reasoning steps or tool calls, in response to a user prompt. To evaluate the success of their trajectories, researchers have developed verifiers, such as LLM judges and process-reward models, to score the quality of each action in an agent's trajectory. Although these heuristic scores can be informative, there are no guarantees of correctness when used to decide whether an agent will yield a successful output. Here, we introduce e-valuator, a method to convert any black-box verifier score into a decision rule with provable control of false alarm rates. We frame the problem of distinguishing successful trajectories (that is, a sequence of actions that will lead to a correct response to the user's prompt) and unsuccessful trajectories as a sequential hypothesis testing problem. E-valuator builds on tools from e-processes to develop a sequential hypothesis test that remains statistically valid at every step of an agent's trajectory, enabling online monitoring of agents over arbitrarily long sequences of actions. Empirically, we demonstrate that e-valuator provides greater statistical power and better false alarm rate control than other strategies across six datasets and three agents. We additionally show that e-valuator can be used for to quickly terminate problematic trajectories and save tokens. Together, e-valuator provides a lightweight, model-agnostic framework that converts verifier heuristics into decisions rules with statistical guarantees, enabling the deployment of more reliable agentic systems.

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arXiv2025

A Bayesian Model for Multi-stage Censoring

Many sequential decision settings in healthcare feature funnel structures characterized by a series of stages, such as screenings or evaluations, where the number of patients who advance to each stage progressively decreases and decisions become increasingly costly. For example, an oncologist may first conduct a breast exam, followed by a mammogram for patients with concerning exams, followed by a biopsy for patients with concerning mammograms. A key challenge is that the ground truth outcome, such as the biopsy result, is only revealed at the end of this funnel. The selective censoring of the ground truth can introduce statistical biases in risk estimation, especially in underserved patient groups, whose outcomes are more frequently censored. We develop a Bayesian model for funnel decision structures, drawing from prior work on selective labels and censoring. We first show in synthetic settings that our model is able to recover the true parameters and predict outcomes for censored patients more accurately than baselines. We then apply our model to a dataset of emergency department visits, where in-hospital mortality is observed only for those who are admitted to either the hospital or ICU. We find that there are gender-based differences in hospital and ICU admissions. In particular, our model estimates that the mortality risk threshold to admit women to the ICU is higher for women (5.1%) than for men (4.5%).

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arXiv2025

Urban Incident Prediction with Graph Neural Networks: Integrating Government Ratings and Crowdsourced Reports

Graph neural networks (GNNs) are widely used in urban spatiotemporal forecasting, such as predicting infrastructure problems. In this setting, government officials wish to know in which neighborhoods incidents like potholes or rodent issues occur. The true state of incidents (e.g., street conditions) for each neighborhood is observed via government inspection ratings. However, these ratings are only conducted for a sparse set of neighborhoods and incident types. We also observe the state of incidents via crowdsourced reports, which are more densely observed but may be biased due to heterogeneous reporting behavior. First, for such settings, we propose a multiview, multioutput GNN-based model that uses both unbiased rating data and biased reporting data to predict the true latent state of incidents. Second, we investigate a case study of New York City urban incidents and collect, standardize, and make publicly available a dataset of 9,615,863 crowdsourced reports and 1,041,415 government inspection ratings over 3 years and across 139 types of incidents. Finally, we show on both real and semi-synthetic data that our model can better predict the latent state compared to models that use only reporting data or models that use only rating data, especially when rating data is sparse and reports are predictive of ratings. We also quantify demographic biases in crowdsourced reporting, e.g., higher-income neighborhoods report problems at higher rates. Our analysis showcases a widely applicable approach for latent state prediction using heterogeneous, sparse, and biased data.

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arXiv2025

Efficiently Batching Unambiguous Interactive Proofs

We show that if a language $L$ admits a public-coin unambiguous interactive proof (UIP) with round complexity $\ell$, where $a$ bits are communicated per round, then the batch language $L^{\otimes k}$, i.e. the set of $k$-tuples of statements all belonging to $L$, has an unambiguous interactive proof with round complexity $\ell\cdot\mathsf{polylog}(k)$, per-round communication of $a\cdot \ell\cdot\mathsf{polylog}(k) + \mathsf{poly}(\ell)$ bits, assuming the verifier in the $\mathsf{UIP}$ has depth bounded by $\mathsf{polylog}(k)$. Prior to this work, the best known batch $\mathsf{UIP}$ for $L^{\otimes{k}}$ required communication complexity at least $(\mathsf{poly}(a)\cdot k^ε + k) \cdot \ell^{1/ε}$ for any arbitrarily small constant $ε>0$ (Reingold-Rothblum-Rothblum, STOC 2016). As a corollary of our result, we obtain a doubly efficient proof system, that is, a proof system whose proving overhead is polynomial in the time of the underlying computation, for any language computable in polynomial space and in time at most $n^{O\left(\sqrt{\frac{\log n}{\log\log n}}\right)}$. This expands the state of the art of doubly efficient proof systems: prior to our work, such systems were known for languages computable in polynomial space and in time $n^{({\log n})^δ}$ for a small $δ>0$ significantly smaller than $1/2$ (Reingold-Rothblum-Rothblum, STOC 2016).

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arXiv2025

Evaluating multiple models using labeled and unlabeled data

It remains difficult to evaluate machine learning classifiers in the absence of a large, labeled dataset. While labeled data can be prohibitively expensive or impossible to obtain, unlabeled data is plentiful. Here, we introduce Semi-Supervised Model Evaluation (SSME), a method that uses both labeled and unlabeled data to evaluate machine learning classifiers. SSME is the first evaluation method to take advantage of the fact that: (i) there are frequently multiple classifiers for the same task, (ii) continuous classifier scores are often available for all classes, and (iii) unlabeled data is often far more plentiful than labeled data. The key idea is to use a semi-supervised mixture model to estimate the joint distribution of ground truth labels and classifier predictions. We can then use this model to estimate any metric that is a function of classifier scores and ground truth labels (e.g., accuracy or expected calibration error). We present experiments in four domains where obtaining large labeled datasets is often impractical: (1) healthcare, (2) content moderation, (3) molecular property prediction, and (4) image annotation. Our results demonstrate that SSME estimates performance more accurately than do competing methods, reducing error by 5.1x relative to using labeled data alone and 2.4x relative to the next best competing method. SSME also improves accuracy when evaluating performance across subsets of the test distribution (e.g., specific demographic subgroups) and when evaluating the performance of language models.

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arXiv2025

AI-based Methods for Simulating, Sampling, and Predicting Protein Ensembles

Advances in deep learning have opened an era of abundant and accurate predicted protein structures; however, similar progress in protein ensembles has remained elusive. This review highlights several recent research directions towards AI-based predictions of protein ensembles, including coarse-grained force fields, generative models, multiple sequence alignment perturbation methods, and modeling of ensemble descriptors. An emphasis is placed on realistic assessments of the technological maturity of current methods, the strengths and weaknesses of broad families of techniques, and promising machine learning frameworks at an early stage of development. We advocate for "closing the loop" between model training, simulation, and inference to overcome challenges in training data availability and to enable the next generation of models.

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arXiv2024

Generative Modeling of Molecular Dynamics Trajectories

Molecular dynamics (MD) is a powerful technique for studying microscopic phenomena, but its computational cost has driven significant interest in the development of deep learning-based surrogate models. We introduce generative modeling of molecular trajectories as a paradigm for learning flexible multi-task surrogate models of MD from data. By conditioning on appropriately chosen frames of the trajectory, we show such generative models can be adapted to diverse tasks such as forward simulation, transition path sampling, and trajectory upsampling. By alternatively conditioning on part of the molecular system and inpainting the rest, we also demonstrate the first steps towards dynamics-conditioned molecular design. We validate the full set of these capabilities on tetrapeptide simulations and show that our model can produce reasonable ensembles of protein monomers. Altogether, our work illustrates how generative modeling can unlock value from MD data towards diverse downstream tasks that are not straightforward to address with existing methods or even MD itself. Code is available at https://github.com/bjing2016/mdgen.

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arXiv2024

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 at https://github.com/bjing2016/alphaflow.

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arXiv2024

Equivariant Scalar Fields for Molecular Docking with Fast Fourier Transforms

Molecular docking is critical to structure-based virtual screening, yet the throughput of such workflows is limited by the expensive optimization of scoring functions involved in most docking algorithms. We explore how machine learning can accelerate this process by learning a scoring function with a functional form that allows for more rapid optimization. Specifically, we define the scoring function to be the cross-correlation of multi-channel ligand and protein scalar fields parameterized by equivariant graph neural networks, enabling rapid optimization over rigid-body degrees of freedom with fast Fourier transforms. The runtime of our approach can be amortized at several levels of abstraction, and is particularly favorable for virtual screening settings with a common binding pocket. We benchmark our scoring functions on two simplified docking-related tasks: decoy pose scoring and rigid conformer docking. Our method attains similar but faster performance on crystal structures compared to the widely-used Vina and Gnina scoring functions, and is more robust on computationally predicted structures. Code is available at https://github.com/bjing2016/scalar-fields.

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arXiv2024

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 at https://github.com/HannesStark/dirichlet-flow-matching.

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arXiv2023

EigenFold: Generative Protein Structure Prediction with Diffusion Models

Protein structure prediction has reached revolutionary levels of accuracy on single structures, yet distributional modeling paradigms are needed to capture the conformational ensembles and flexibility that underlie biological function. Towards this goal, we develop EigenFold, a diffusion generative modeling framework for sampling a distribution of structures from a given protein sequence. We define a diffusion process that models the structure as a system of harmonic oscillators and which naturally induces a cascading-resolution generative process along the eigenmodes of the system. On recent CAMEO targets, EigenFold achieves a median TMScore of 0.84, while providing a more comprehensive picture of model uncertainty via the ensemble of sampled structures relative to existing methods. We then assess EigenFold's ability to model and predict conformational heterogeneity for fold-switching proteins and ligand-induced conformational change. Code is available at https://github.com/bjing2016/EigenFold.

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arXiv2023

Scalable and Privacy-Preserving Federated Principal Component Analysis

Principal component analysis (PCA) is an essential algorithm for dimensionality reduction in many data science domains. We address the problem of performing a federated PCA on private data distributed among multiple data providers while ensuring data confidentiality. Our solution, SF-PCA, is an end-to-end secure system that preserves the confidentiality of both the original data and all intermediate results in a passive-adversary model with up to all-but-one colluding parties. SF-PCA jointly leverages multiparty homomorphic encryption, interactive protocols, and edge computing to efficiently interleave computations on local cleartext data with operations on collectively encrypted data. SF-PCA obtains results as accurate as non-secure centralized solutions, independently of the data distribution among the parties. It scales linearly or better with the dataset dimensions and with the number of data providers. SF-PCA is more precise than existing approaches that approximate the solution by combining local analysis results, and between 3x and 250x faster than privacy-preserving alternatives based solely on secure multiparty computation or homomorphic encryption. Our work demonstrates the practical applicability of secure and federated PCA on private distributed datasets.

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arXiv2023

Causally-guided Regularization of Graph Attention Improves Generalizability

Graph attention networks estimate the relational importance of node neighbors to aggregate relevant information over local neighborhoods for a prediction task. However, the inferred attentions are vulnerable to spurious correlations and connectivity in the training data, hampering the generalizability of the model. We introduce CAR, a general-purpose regularization framework for graph attention networks. Embodying a causal inference approach, CAR aligns the attention mechanism with the causal effects of active interventions on graph connectivity in a scalable manner. CAR is compatible with a variety of graph attention architectures, and we show that it systematically improves generalizability on various node classification tasks. Our ablation studies indicate that CAR hones in on the aspects of graph structure most pertinent to the prediction (e.g., homophily), and does so more effectively than alternative approaches. Finally, we also show that CAR enhances interpretability of attention weights by accentuating node-neighbor relations that point to causal hypotheses. For social media network-sized graphs, a CAR-guided graph rewiring approach could allow us to combine the scalability of graph convolutional methods with the higher performance of graph attention.

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arXiv2022

Granger causal inference on DAGs identifies genomic loci regulating transcription

When a dynamical system can be modeled as a sequence of observations, Granger causality is a powerful approach for detecting predictive interactions between its variables. However, traditional Granger causal inference has limited utility in domains where the dynamics need to be represented as directed acyclic graphs (DAGs) rather than as a linear sequence, such as with cell differentiation trajectories. Here, we present GrID-Net, a framework based on graph neural networks with lagged message passing for Granger causal inference on DAG-structured systems. Our motivating application is the analysis of single-cell multimodal data to identify genomic loci that mediate the regulation of specific genes. To our knowledge, GrID-Net is the first single-cell analysis tool that accounts for the temporal lag between a genomic locus becoming accessible and its downstream effect on a target gene's expression. We applied GrID-Net on multimodal single-cell assays that profile chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) in the same cell and show that it dramatically outperforms existing methods for inferring regulatory locus-gene links, achieving up to 71% greater agreement with independent population genetics-based estimates. By extending Granger causality to DAG-structured dynamical systems, our work unlocks new domains for causal analyses and, more specifically, opens a path towards elucidating gene regulatory interactions relevant to cellular differentiation and complex human diseases at unprecedented scale and resolution.

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arXiv2022

Enriching and Characterizing T-Cell Repertoires from 3' Barcoded Single-Cell Whole Transcriptome Amplification Products

Antigen-specific T cells play an essential role in immunoregulation and diseases such as cancer. Characterizing the T cell receptor (TCR) sequences that encode T cell specificity is critical for elucidating the antigenic determinants of immunological diseases and designing therapeutic remedies. However, methods of obtaining single-cell TCR sequencing data are labor and cost intensive, requiring cell sorting and full length single-cell RNA-sequencing (scRNA-seq). New high-throughput 3' cell-barcoding scRNA-seq methods can simplify and scale this process; however, they do not routinely capture TCR sequences during library preparation and sequencing. While 5' cell-barcoding scRNA-seq methods can be used to examine TCR repertoire at single-cell resolution, it requires specialized reagents which cannot be applied to samples previously processed using 3' cell-barcoding methods. Here, we outline a method for sequencing TCR$α$ and TCR$β$ transcripts from samples already processed using 3' cell-barcoding scRNA-seq platforms, ensuring TCR recovery at a single-cell resolution. In short, a fraction of the 3' barcoded whole transcriptome amplification (WTA) product typically used to generate a massively parallel 3' scRNA-seq library is enriched for TCR transcripts using biotinylated probes, and further amplified using the same universal primer sequence from WTA. Primer extension using TCR V-region primers and targeted PCR amplification results in a 3' barcoded single-cell CDR3-enriched library that can be sequenced with custom sequencing primers. Coupled with 3' scRNA-seq of the same WTA, this method enables simultaneous analysis of single-cell transcriptomes and TCR sequences which can help interpret inherent heterogeneity among antigen-specific T cells and salient disease biology. This method can be adapted to enrich other transcripts of interest from 3' and 5' barcoded WTA libraries.

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arXiv2021

Exploring generative atomic models in cryo-EM reconstruction

Cryo-EM reconstruction algorithms seek to determine a molecule's 3D density map from a series of noisy, unlabeled 2D projection images captured with an electron microscope. Although reconstruction algorithms typically model the 3D volume as a generic function parameterized as a voxel array or neural network, the underlying atomic structure of the protein of interest places well-defined physical constraints on the reconstructed structure. In this work, we exploit prior information provided by an atomic model to reconstruct distributions of 3D structures from a cryo-EM dataset. We propose Cryofold, a generative model for a continuous distribution of 3D volumes based on a coarse-grained model of the protein's atomic structure, with radial basis functions used to model atom locations and their physics-based constraints. Although the reconstruction objective is highly non-convex when formulated in terms of atomic coordinates (similar to the protein folding problem), we show that gradient descent-based methods can reconstruct a continuous distribution of atomic structures when initialized from a structure within the underlying distribution. This approach is a promising direction for integrating biophysical simulation, learned neural models, and experimental data for 3D protein structure determination.

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