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Tristan Bepler

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5 papers

2 author rows

NeurIPS Conference 2025 Conference Paper

Understanding protein function with a multimodal retrieval-augmented foundation model

Timothy Truong Jr
Tristan Bepler

Protein language models (PLMs) learn probability distributions over natural protein sequences. By learning from hundreds of millions of natural protein sequences, protein understanding and design capabilities emerge. Recent works have shown that scaling these models improves structure prediction, but does not seem to improve mutation understanding and representation quality for protein function prediction. We introduce PoET-2, a multimodal, retrieval-augmented protein foundation model that incorporates in-context learning of family-specific evolutionary constraints with optional structure conditioning to learn generative distributions over protein sequences. PoET-2 uses a hierarchical transformer encoder that is equivariant to sequence context ordering and a dual decoder architecture with both causal and masked language modeling objectives, allowing PoET-2 to operate in both fully generative and bidirectional representation learning modes. PoET-2 achieves state-of-the-art performance on zero-shot variant effect prediction, excelling at scoring variants with multiple mutations and challenging indel mutations. In supervised settings, PoET-2 embeddings outperform previous methods for learning sequence-function relationships, especially with small datasets. This work highlights the benefits of combining retrieval augmentation with multimodal, family-centric modeling for advancing protein foundation models.

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NeurIPS Conference 2023 Conference Paper

PoET: A generative model of protein families as sequences-of-sequences

Timothy Truong Jr
Tristan Bepler

Generative protein language models are a natural way to design new proteins with desired functions. However, current models are either difficult to direct to produce a protein from a specific family of interest, or must be trained on a large multiple sequence alignment (MSA) from the specific family of interest, making them unable to benefit from transfer learning across families. To address this, we propose P r o tein E volutionary T ransformer (PoET), an autoregressive generative model of whole protein families that learns to generate sets of related proteins as sequences-of-sequences across tens of millions of natural protein sequence clusters. PoET can be used as a retrieval-augmented language model to generate and score arbitrary modifications conditioned on any protein family of interest, and can extrapolate from short context lengths to generalize well even for small families. This is enabled by a unique Transformer layer; we model tokens sequentially within sequences while attending between sequences order invariantly, allowing PoET to scale to context lengths beyond those used during training. In extensive experiments on deep mutational scanning datasets, we show that PoET outperforms existing protein language models and evolutionary sequence models for variant function prediction across proteins of all MSA depths. We also demonstrate PoET's ability to controllably generate new protein sequences.

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NeurIPS Conference 2022 Conference Paper

Unsupervised Object Representation Learning using Translation and Rotation Group Equivariant VAE

Alireza Nasiri
Tristan Bepler

In many imaging modalities, objects of interest can occur in a variety of locations and poses (i. e. are subject to translations and rotations in 2d or 3d), but the location and pose of an object does not change its semantics (i. e. the object's essence). That is, the specific location and rotation of an airplane in satellite imagery, or the 3d rotation of a chair in a natural image, or the rotation of a particle in a cryo-electron micrograph, do not change the intrinsic nature of those objects. Here, we consider the problem of learning semantic representations of objects that are invariant to pose and location in a fully unsupervised manner. We address shortcomings in previous approaches to this problem by introducing TARGET-VAE, a translation and rotation group-equivariant variational autoencoder framework. TARGET-VAE combines three core innovations: 1) a rotation and translation group-equivariant encoder architecture, 2) a structurally disentangled distribution over latent rotation, translation, and a rotation-translation-invariant semantic object representation, which are jointly inferred by the approximate inference network, and 3) a spatially equivariant generator network. In comprehensive experiments, we show that TARGET-VAE learns disentangled representations without supervision that significantly improve upon, and avoid the pathologies of, previous methods. When trained on images highly corrupted by rotation and translation, the semantic representations learned by TARGET-VAE are similar to those learned on consistently posed objects, dramatically improving clustering in the semantic latent space. Furthermore, TARGET-VAE is able to perform remarkably accurate unsupervised pose and location inference. We expect methods like TARGET-VAE will underpin future approaches for unsupervised object generation, pose prediction, and object detection. Our code is available at https: //github. com/SMLC-NYSBC/TARGET-VAE.

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ICLR Conference 2020 Conference Paper

Reconstructing continuous distributions of 3D protein structure from cryo-EM images

Ellen D. Zhong
Tristan Bepler
Joseph H. Davis
Bonnie Berger

Cryo-electron microscopy (cryo-EM) is a powerful technique for determining the structure of proteins and other macromolecular complexes at near-atomic resolution. In single particle cryo-EM, the central problem is to reconstruct the 3D structure of a macromolecule from $10^{4-7}$ noisy and randomly oriented 2D projection images. However, the imaged protein complexes may exhibit structural variability, which complicates reconstruction and is typically addressed using discrete clustering approaches that fail to capture the full range of protein dynamics. Here, we introduce a novel method for cryo-EM reconstruction that extends naturally to modeling continuous generative factors of structural heterogeneity. This method encodes structures in Fourier space using coordinate-based deep neural networks, and trains these networks from unlabeled 2D cryo-EM images by combining exact inference over image orientation with variational inference for structural heterogeneity. We demonstrate that the proposed method, termed cryoDRGN, can perform ab-initio reconstruction of 3D protein complexes from simulated and real 2D cryo-EM image data. To our knowledge, cryoDRGN is the first neural network-based approach for cryo-EM reconstruction and the first end-to-end method for directly reconstructing continuous ensembles of protein structures from cryo-EM images.

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NeurIPS Conference 2019 Conference Paper

Explicitly disentangling image content from translation and rotation with spatial-VAE

Tristan Bepler
Ellen Zhong
Kotaro Kelley
Edward Brignole
Bonnie Berger

Given an image dataset, we are often interested in finding data generative factors that encode semantic content independently from pose variables such as rotation and translation. However, current disentanglement approaches do not impose any specific structure on the learned latent representations. We propose a method for explicitly disentangling image rotation and translation from other unstructured latent factors in a variational autoencoder (VAE) framework. By formulating the generative model as a function of the spatial coordinate, we make the reconstruction error differentiable with respect to latent translation and rotation parameters. This formulation allows us to train a neural network to perform approximate inference on these latent variables while explicitly constraining them to only represent rotation and translation. We demonstrate that this framework, termed spatial-VAE, effectively learns latent representations that disentangle image rotation and translation from content and improves reconstruction over standard VAEs on several benchmark datasets, including applications to modeling continuous 2-D views of proteins from single particle electron microscopy and galaxies in astronomical images.

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