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Structure-based drug design (SBDD) faces a fundamental scaling fidelity dilemma: rich pocket-aware conditioning captures interaction geometry but can be costly, often scales quadratically ($O(L^2)$) or worse with protein length ($L$), while…

Machine Learning · Computer Science 2026-02-02 Samyak Sanghvi , Nishant Ranjan , Tarak Karmakar

The remarkable structural diversity of modern proteins reflects millions of years of evolution, during which sequence space has expanded while many structural features remain conserved. This conservation is evident not only among homologous…

Inverse Protein Folding (IPF) is a critical subtask in the field of protein design, aiming to engineer amino acid sequences capable of folding correctly into a specified three-dimensional (3D) conformation. Although substantial progress has…

Computation and Language · Computer Science 2025-05-20 Yanting Li , Jiyue Jiang , Zikang Wang , Ziqian Lin , Dongchen He , Yuheng Shan , Yanruisheng Shao , Jiayi Li , Xiangyu Shi , Jiuming Wang , Yanyu Chen , Yimin Fan , Han Li , Yu Li

Tokens serve as the basic units of representation in DNA language models (DNALMs), yet their design remains underexplored. Unlike natural language, DNA lacks inherent token boundaries or predefined compositional rules, making tokenization a…

Machine Learning · Computer Science 2026-04-13 Nan Huang , Xiaoxiao Zhou , Junxia Cui , Mario Tapia-Pacheco , Tiffany Amariuta , Yang Li , Jingbo Shang

Tokenization is a hardcoded compression step which remains in the training pipeline of Large Language Models (LLMs), despite a general trend towards architectures becoming increasingly end-to-end. Prior work has shown promising results at…

Machine Learning · Computer Science 2026-02-17 Sam Dauncey , Roger Wattenhofer

The evolutionary trajectory of a protein through sequence space is constrained by function and three-dimensional (3D) structure. Residues in spatial proximity tend to co-evolve, yet attempts to invert the evolutionary record to identify…

Biomolecules · Quantitative Biology 2015-03-13 Debora S. Marks , Lucy J. Colwell , Robert Sheridan , Thomas A. Hopf , Andrea Pagnani , Riccardo Zecchina , Chris Sander

Molecular representation learning methods typically tokenize molecules as individual atoms or use rigid, rule-based fragment decompositions, limiting their ability to capture meaningful chemical substructure context. We introduce…

Machine Learning · Computer Science 2026-05-26 Ankur Samanta , Rohan Gupta , Aditi Misra , Christian McIntosh Clarke , Jayakumar Rajadas

Modeling genomic sequences faces two unsolved challenges: the information density varies widely across different regions, while there is no clearly defined minimum vocabulary unit. Relying on either four primitive bases or independently…

Genomics · Quantitative Biology 2025-11-20 Siyuan Li , Kai Yu , Anna Wang , Zicheng Liu , Chang Yu , Jingbo Zhou , Qirong Yang , Yucheng Guo , Xiaoming Zhang , Stan Z. Li

How proteins fold remains a central unsolved problem in biology. While the idea of a folding code embedded in the amino acid sequence was introduced more than 6 decades ago, this code remains undefined. While we now have powerful predictive…

Biomolecules · Quantitative Biology 2025-11-04 Carlos Bustamante , Christian Kaiser , Erik Lindahl , Robert Sosa , Giovanni Volpe

Vector-Quantized Image Modeling (VQIM) is a fundamental research problem in image synthesis, which aims to represent an image with a discrete token sequence. Existing studies effectively address this problem by learning a discrete codebook…

Computer Vision and Pattern Recognition · Computer Science 2024-03-18 Baoquan Zhang , Huaibin Wang , Luo Chuyao , Xutao Li , Liang Guotao , Yunming Ye , Xiaochen Qi , Yao He

In this article, we present a fresh perspective on language, combining ideas from various sources, but mixed in a new synthesis. As in the minimalist program, the question is whether we can formulate an elegant formalism, a universal…

Computation and Language · Computer Science 2023-03-10 Loe Feijs

The differing representation spaces required for visual understanding and generation pose a challenge in unifying them within the autoregressive paradigm of large language models. A vision tokenizer trained for reconstruction excels at…

Computer Vision and Pattern Recognition · Computer Science 2026-04-21 Wei Song , Yuran Wang , Zijia Song , Yadong Li , Zenan Zhou , Long Chen , Jianhua Xu , Jiaqi Wang , Kaicheng Yu

As a cornerstone in language modeling, tokenization involves segmenting text inputs into pre-defined atomic units. Conventional statistical tokenizers often disrupt constituent boundaries within words, thereby corrupting semantic…

Computation and Language · Computer Science 2025-07-11 Qingyang Zhu , Xiang Hu , Pengyu Ji , Wei Wu , Kewei Tu

Attention-based models trained on protein sequences have demonstrated incredible success at classification and generation tasks relevant for artificial intelligence-driven protein design. However, we lack a sufficient understanding of how…

Machine Learning · Computer Science 2022-06-29 Erik Nijkamp , Jeffrey Ruffolo , Eli N. Weinstein , Nikhil Naik , Ali Madani

Image tokenizers form the foundation of modern text-to-image generative models but are notoriously difficult to train. Furthermore, most existing text-to-image models rely on large-scale, high-quality private datasets, making them…

Computer Vision and Pattern Recognition · Computer Science 2025-08-05 Dongwon Kim , Ju He , Qihang Yu , Chenglin Yang , Xiaohui Shen , Suha Kwak , Liang-Chieh Chen

We present VoxBind, a new score-based generative model for 3D molecules conditioned on protein structures. Our approach represents molecules as 3D atomic density grids and leverages a 3D voxel-denoising network for learning and generation.…

Machine Learning · Computer Science 2024-07-03 Pedro O. Pinheiro , Arian Jamasb , Omar Mahmood , Vishnu Sresht , Saeed Saremi

Genomic foundation models have the potential to decode DNA syntax, yet face a fundamental tradeoff in their input representation. Standard fixed-vocabulary tokenizers fragment biologically meaningful motifs such as codons and regulatory…

Proteins in complex with small molecule ligands represent the core of structure-based drug discovery. However, three-dimensional representations are absent from most deep-learning-based generative models. We here present a graph-based…

Biomolecules · Quantitative Biology 2022-04-07 Seung-gu Kang , Jeffrey K. Weber , Joseph A. Morrone , Leili Zhang , Tien Huynh , Wendy D. Cornell

Learning from 3D protein structures has gained wide interest in protein modeling and structural bioinformatics. Unfortunately, the number of available structures is orders of magnitude lower than the training data sizes commonly used in…

Biomolecules · Quantitative Biology 2022-06-01 Pedro Hermosilla , Timo Ropinski

Proteins are sequences of amino acids that serve as the basic building blocks of living organisms. Despite rapidly growing databases documenting structural and functional information for various protein sequences, our understanding of…

Biomolecules · Quantitative Biology 2025-01-06 Weihang Dai
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