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Diffusion models offer a powerful means of capturing the manifold of realistic protein structures, enabling rapid design for protein engineering tasks. However, existing approaches observe critical failure modes when precise constraints are…

Biomolecules · Quantitative Biology 2026-03-27 Jacob K. Christopher , Austin Seamann , Jingyi Cui , Sagar Khare , Ferdinando Fioretto

The diverse nature of protein prediction tasks has traditionally necessitated specialized models, hindering the development of broadly applicable and computationally efficient Protein Language Models (PLMs). In this work, we introduce…

Proteins perform critical processes in all living systems: converting solar energy into chemical energy, replicating DNA, as the basis of highly performant materials, sensing and much more. While an incredible range of functionality has…

Biomolecules · Quantitative Biology 2021-09-29 Leonardo V. Castorina , Rokas Petrenas , Kartic Subr , Christopher W. Wood

Multi-objective optimization (MOO) arises in many real-world applications where trade-offs between competing objectives must be carefully balanced. In the offline setting, where only a static dataset is available, the main challenge is…

Machine Learning · Computer Science 2026-02-16 Jatan Shrestha , Santeri Heiskanen , Kari Hepola , Severi Rissanen , Pekka Jääskeläinen , Joni Pajarinen

Protein sequence design methods have demonstrated strong performance in sequence generation for de novo protein design. However, as the training objective was sequence recovery, it does not guarantee designability--the likelihood that a…

Machine Learning · Computer Science 2025-06-03 Fanglei Xue , Andrew Kubaney , Zhichun Guo , Joseph K. Min , Ge Liu , Yi Yang , David Baker

To fully leverage the capabilities of diffusion models, we are often interested in optimizing downstream reward functions during inference. While numerous algorithms for reward-guided generation have been recently proposed due to their…

Machine Learning · Computer Science 2025-04-18 Masatoshi Uehara , Xingyu Su , Yulai Zhao , Xiner Li , Aviv Regev , Shuiwang Ji , Sergey Levine , Tommaso Biancalani

Intrinsically disordered regions of proteins play a crucial role in cell signaling and drug discovery. However, their high structural flexibility makes accurate residue-level prediction challenging. Existing methods often rely on…

Neural and Evolutionary Computing · Computer Science 2026-03-09 Shaokuan Wang , Pengshan Cui , Yining Qian , An-Yang Lu , Xianpeng Wang

Diffusion models have achieved promising results for Structure-Based Drug Design (SBDD). Nevertheless, high-quality protein subpocket and ligand data are relatively scarce, which hinders the models' generation capabilities. Recently, Direct…

Biomolecules · Quantitative Biology 2026-02-11 Xiwei Cheng , Xiangxin Zhou , Yuwei Yang , Yu Bao , Quanquan Gu

Proteins perform their biological functions through three-dimensional structures encoded by amino acid sequences, and ligand-binding protein co-design requires models that generate sequence-structure compatible proteins under explicit…

Biomolecules · Quantitative Biology 2026-05-28 Chen Wei , Fanding Xu , Minghao Sun , Zhiyuan Liu , Lin Wang , Tianrui Jia , Yihang Zhou , Yang Zhang

The inverse folding problem, aiming to design amino acid sequences that fold into desired three-dimensional structures, is pivotal for various biotechnological applications. Here, we introduce a novel approach leveraging Direct Preference…

Machine Learning · Computer Science 2025-06-04 Junde Xu , Zijun Gao , Xinyi Zhou , Jie Hu , Xingyi Cheng , Le Song , Guangyong Chen , Pheng-Ann Heng , Jiezhong Qiu

Directed evolution is a versatile technique in protein engineering that mimics the process of natural selection by iteratively alternating between mutagenesis and screening in order to search for sequences that optimize a given property of…

Biomolecules · Quantitative Biology 2024-05-02 Lixue Cheng , Ziyi Yang , Changyu Hsieh , Benben Liao , Shengyu Zhang

Generating protein sequences that fold into a intended 3D structure is a fundamental step in de novo protein design. De facto methods utilize autoregressive generation, but this eschews higher order interactions that could be exploited to…

Biomolecules · Quantitative Biology 2023-12-06 John J. Yang , Jason Yim , Regina Barzilay , Tommi Jaakkola

Learning meaningful protein representation is important for a variety of biological downstream tasks such as structure-based drug design. Having witnessed the success of protein sequence pretraining, pretraining for structural data which is…

Machine Learning · Computer Science 2023-02-23 Yufei Huang , Lirong Wu , Haitao Lin , Jiangbin Zheng , Ge Wang , Stan Z. Li

Generating novel and functional protein sequences is critical to a wide range of applications in biology. Recent advancements in conditional diffusion models have shown impressive empirical performance in protein generation tasks. However,…

Machine Learning · Computer Science 2025-12-04 Zinan Ling , Yi Shi , Brett McKinney , Da Yan , Yang Zhou , Bo Hui

Monte Carlo Tree Diffusion (MCTD) integrates diffusion models with structured tree search to enable effective trajectory exploration through stepwise reasoning. However, MCTD remains fundamentally limited by training trajectory lengths.…

Machine Learning · Computer Science 2026-01-07 Jaesik Yoon , Hyeonseo Cho , Sungjin Ahn

Generative modeling of discrete data underlies important applications spanning text-based agents like ChatGPT to the design of the very building blocks of life in protein sequences. However, application domains need to exert control over…

Offline multi-objective optimization aims to identify Pareto-optimal solutions given a dataset of designs and their objective values. In this work, we propose a preference-guided diffusion model that generates Pareto-optimal designs by…

Machine Learning · Computer Science 2025-12-19 Yashas Annadani , Syrine Belakaria , Stefano Ermon , Stefan Bauer , Barbara E Engelhardt

Pareto front profiling in multi-objective optimization (MOO), i.e., finding a diverse set of Pareto optimal solutions, is challenging, especially with expensive objectives that require training a neural network. Typically, in MOO for neural…

Machine Learning · Computer Science 2025-02-06 Rhea Sanjay Sukthanker , Arber Zela , Benedikt Staffler , Samuel Dooley , Josif Grabocka , Frank Hutter

Dual-target molecule generation, which focuses on discovering compounds capable of interacting with two target proteins, has garnered significant attention due to its potential for improving therapeutic efficiency, safety and resistance…

Machine Learning · Computer Science 2026-04-28 Thibaud Southiratn , Bonil Koo , Yijingxiu Lu , Sun Kim

Deep learning models form one of the most powerful machine learning models for the extraction of important features. Most of the designs of deep neural models, i.e., the initialization of parameters, are still manually tuned. Hence,…

Machine Learning · Computer Science 2023-05-18 Mrittika Chakraborty , Wreetbhas Pal , Sanghamitra Bandyopadhyay , Ujjwal Maulik