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How can Large Language Models (LLMs) be aligned with human intentions and values? A typical solution is to gather human preference on model outputs and finetune the LLMs accordingly while ensuring that updates do not deviate too far from a…

Computation and Language · Computer Science 2024-05-28 Hung Le , Quan Tran , Dung Nguyen , Kien Do , Saloni Mittal , Kelechi Ogueji , Svetha Venkatesh

Designing proteins with desired functions or properties represents a core goal in synthetic biology and drug discovery. Recent advances in protein language models (PLMs) have enabled the generation of highly designable protein sequences,…

Machine Learning · Computer Science 2026-05-12 Yulin Zhang , He Cao , Zihao Jiang , Chenyi Zi , Zhipeng Zhou , Zijing Liu , Yu Li , Jia Li , Ziqi Gao

Direct Preference Optimization (DPO) is an effective approach for aligning protein language models with experimental design goals. However, DPO faces a scalability bottleneck: the number of possible training pairs grows quadratically with…

Machine Learning · Computer Science 2025-11-27 Constance Ferragu , Jonathan D. Ziegler , Nicolas Deutschmann , Arthur Lindoulsi , Eli Bixby , Cradle ML Team

Direct Preference Optimization (DPO) and its variants have become the de facto standards for aligning large language models (LLMs) with human preferences or specific goals. However, DPO requires high-quality preference data and suffers from…

Machine Learning · Computer Science 2024-11-12 Zhuotong Chen , Fang Liu , Jennifer Zhu , Wanyu Du , Yanjun Qi

Molecular language modeling is an effective approach to generating novel chemical structures. However, these models do not \emph{a priori} encode certain preferences a chemist may desire. We investigate the use of fine-tuning using Direct…

Machine Learning · Statistics 2023-10-20 Ryan Park , Ryan Theisen , Navriti Sahni , Marcel Patek , Anna Cichońska , Rayees Rahman

Protein sequence design must balance designability, defined as the ability to recover a target backbone, with multiple, often competing, developability properties such as solubility, thermostability, and expression. Existing approaches…

Machine Learning · Computer Science 2026-03-11 Xiaoyang Hou , Junqi Liu , Chence Shi , Xin Liu , Zhi Yang , Jian Tang

Large Language Models (LLMs) have become pivotal in advancing natural language processing, yet their potential to perpetuate biases poses significant concerns. This paper introduces a new framework employing Direct Preference Optimization…

Computation and Language · Computer Science 2024-07-22 Ahmed Allam

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

For aligning large language models (LLMs), prior work has leveraged reinforcement learning via human feedback (RLHF) or variations of direct preference optimization (DPO). While DPO offers a simpler framework based on maximum likelihood…

Artificial Intelligence · Computer Science 2025-05-27 Anirudhan Badrinath , Prabhat Agarwal , Jiajing Xu

Direct Preference Optimization (DPO) is broadly utilized for aligning Large Language Models (LLMs) with human values because of its flexibility. Despite its effectiveness, it has been observed that the capability of DPO to generate…

Machine Learning · Computer Science 2025-05-20 Wenqiao Zhu , Ji Liu , Lulu Wang , Jun Wu , Yulun Zhang

Inverse folding models play an important role in structure-based design by predicting amino acid sequences that fold into desired reference structures. Models like ProteinMPNN, a message-passing encoder-decoder model, are trained to…

Machine Learning · Computer Science 2026-05-12 Ryan Park , Darren J. Hsu , C. Brian Roland , Maria Korshunova , Chen Tessler , Shie Mannor , Olivia Viessmann , Bruno Trentini

Fine-tuning is integral for aligning large language models (LLMs) with human preferences. Multiple-Reference Preference Optimization (MRPO) builds on Direct Preference Optimization (DPO) by fine-tuning LLMs on preference datasets while…

Machine Learning · Computer Science 2025-12-12 Skyler Wu , Aymen Echarghaoui

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

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

Direct Preference Optimization (DPO) has become a prominent method for aligning Large Language Models (LLMs) with human preferences. While DPO has enabled significant progress in aligning English LLMs, multilingual preference alignment is…

Computation and Language · Computer Science 2025-06-06 Wen Yang , Junhong Wu , Chen Wang , Chengqing Zong , Jiajun Zhang

Recently, preference optimization methods such as DPO have significantly enhanced large language models (LLMs) in wide tasks including dialogue and question-answering. However, current methods fail to account for the varying difficulty…

Computation and Language · Computer Science 2024-12-31 Jingyuan Ma , Rui Li , Zheng Li , Lei Sha , Zhifang Sui

The widespread application of large language models (LLMs) raises increasing demands on ensuring safety or imposing constraints, such as reducing harmful content and adhering to predefined rules. While there have been several works studying…

Machine Learning · Computer Science 2026-02-13 Yihan Du , Seo Taek Kong , R. Srikant

Direct Preference Optimization (DPO) has become a widely used training method for the instruction fine-tuning of large language models (LLMs). In this work, we explore an under-investigated aspect of DPO - its dependency on the reference…

Computation and Language · Computer Science 2024-08-23 Yixin Liu , Pengfei Liu , Arman Cohan

Recent alignment methods based on Direct Preference Optimization (DPO) reformulate preference learning as supervised optimization over pairwise comparisons, offering improved efficiency and stability over reinforcement learning from human…

Machine Learning · Computer Science 2026-01-22 Yuhui Sun , Xiyao Wang , Zixi Li , YiTian Ding , Tianyang Ling , Jialuo Chen , Tianyi Yu , Zhenlong Yuan , Jinman Zhao

Multi-objective preference alignment of large language models (LLMs) is critical for developing AI systems that are more configurable, personalizable, helpful, and safe. However, optimizing model outputs to satisfy diverse objectives with…

Computation and Language · Computer Science 2025-03-04 Raghav Gupta , Ryan Sullivan , Yunxuan Li , Samrat Phatale , Abhinav Rastogi
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