J. Zhu

Qizhi Pei, Lijun Wu, Jinhua Zhu et al. · microsoft-research

Accurate prediction of Drug-Target Affinity (DTA) is of vital importance in early-stage drug discovery, facilitating the identification of drugs that can effectively interact with specific targets and regulate their activities. While wet experiments remain the most reliable method, they are time-consuming and resource-intensive, resulting in limited data availability that poses challenges for deep learning approaches. Existing methods have primarily focused on developing techniques based on the available DTA data, without adequately addressing the data scarcity issue. To overcome this challenge, we present the SSM-DTA framework, which incorporates three simple yet highly effective strategies: (1) A multi-task training approach that combines DTA prediction with masked language modeling (MLM) using paired drug-target data. (2) A semi-supervised training method that leverages large-scale unpaired molecules and proteins to enhance drug and target representations. This approach differs from previous methods that only employed molecules or proteins in pre-training. (3) The integration of a lightweight cross-attention module to improve the interaction between drugs and targets, further enhancing prediction accuracy. Through extensive experiments on benchmark datasets such as BindingDB, DAVIS, and KIBA, we demonstrate the superior performance of our framework. Additionally, we conduct case studies on specific drug-target binding activities, virtual screening experiments, drug feature visualizations, and real-world applications, all of which showcase the significant potential of our work. In conclusion, our proposed SSM-DTA framework addresses the data limitation challenge in DTA prediction and yields promising results, paving the way for more efficient and accurate drug discovery processes. Our code is available at $\href{https://github.com/QizhiPei/SSM-DTA}{Github}$.

ByteDance Seed, Yuyu Zhang, Jing Su et al. · bytedance

Code data in large language model (LLM) pretraining is recognized crucial not only for code-related tasks but also for enhancing general intelligence of LLMs. Current open-source LLMs often heavily rely on human effort to produce their code pretraining data, such as employing hand-crafted filtering rules tailored to individual programming languages, or using human-annotated data to train quality filters. However, these approaches are inherently limited in scalability, prone to subjective biases, and costly to extend and maintain across diverse programming languages. To address these challenges, we introduce Seed-Coder, a series of open-source LLMs comprising base, instruct and reasoning models of 8B size, minimizing human involvement in data construction. Our code pretraining data is produced by a model-centric data pipeline, which predominantly leverages LLMs for scoring and filtering code data. The instruct model is further trained via supervised fine-tuning and preference optimization, and the reasoning model leverages Long-Chain-of-Thought (LongCoT) reinforcement learning to improve multi-step code reasoning. Seed-Coder achieves state-of-the-art results among open-source models of similar size and even surpasses some much larger models, demonstrating superior performance in code generation, code completion, code editing, code reasoning, and software engineering tasks.

Jinhua Zhu, Yingce Xia, Lijun Wu et al. · microsoft-research

Molecular representation learning has attracted much attention recently. A molecule can be viewed as a 2D graph with nodes/atoms connected by edges/bonds, and can also be represented by a 3D conformation with 3-dimensional coordinates of all atoms. We note that most previous work handles 2D and 3D information separately, while jointly leveraging these two sources may foster a more informative representation. In this work, we explore this appealing idea and propose a new representation learning method based on a unified 2D and 3D pre-training. Atom coordinates and interatomic distances are encoded and then fused with atomic representations through graph neural networks. The model is pre-trained on three tasks: reconstruction of masked atoms and coordinates, 3D conformation generation conditioned on 2D graph, and 2D graph generation conditioned on 3D conformation. We evaluate our method on 11 downstream molecular property prediction tasks: 7 with 2D information only and 4 with both 2D and 3D information. Our method achieves state-of-the-art results on 10 tasks, and the average improvement on 2D-only tasks is 8.3%. Our method also achieves significant improvement on two 3D conformation generation tasks.

Kaiyuan Gao, Lijun Wu, Jinhua Zhu et al. · microsoft-research

Antibodies are versatile proteins that can bind to pathogens and provide effective protection for human body. Recently, deep learning-based computational antibody design has attracted popular attention since it automatically mines the antibody patterns from data that could be complementary to human experiences. However, the computational methods heavily rely on high-quality antibody structure data, which is quite limited. Besides, the complementarity-determining region (CDR), which is the key component of an antibody that determines the specificity and binding affinity, is highly variable and hard to predict. Therefore, the data limitation issue further raises the difficulty of CDR generation for antibodies. Fortunately, there exists a large amount of sequence data of antibodies that can help model the CDR and alleviate the reliance on structure data. By witnessing the success of pre-training models for protein modeling, in this paper, we develop the antibody pre-training language model and incorporate it into the (antigen-specific) antibody design model in a systemic way. Specifically, we first pre-train an antibody language model based on the sequence data, then propose a one-shot way for sequence and structure generation of CDR to avoid the heavy cost and error propagation from an autoregressive manner, and finally leverage the pre-trained antibody model for the antigen-specific antibody generation model with some carefully designed modules. Through various experiments, we show that our method achieves superior performances over previous baselines on different tasks, such as sequence and structure generation and antigen-binding CDR-H3 design.

Jinhua Zhu, Yingce Xia, Chang Liu et al.

Molecular conformation generation aims to generate three-dimensional coordinates of all the atoms in a molecule and is an important task in bioinformatics and pharmacology. Previous methods usually first predict the interatomic distances, the gradients of interatomic distances or the local structures (e.g., torsion angles) of a molecule, and then reconstruct its 3D conformation. How to directly generate the conformation without the above intermediate values is not fully explored. In this work, we propose a method that directly predicts the coordinates of atoms: (1) the loss function is invariant to roto-translation of coordinates and permutation of symmetric atoms; (2) the newly proposed model adaptively aggregates the bond and atom information and iteratively refines the coordinates of the generated conformation. Our method achieves the best results on GEOM-QM9 and GEOM-Drugs datasets. Further analysis shows that our generated conformations have closer properties (e.g., HOMO-LUMO gap) with the groundtruth conformations. In addition, our method improves molecular docking by providing better initial conformations. All the results demonstrate the effectiveness of our method and the great potential of the direct approach. The code is released at https://github.com/DirectMolecularConfGen/DMCG

Jinhua Zhu, Yingce Xia, Lijun Wu et al.

Improving sample efficiency is a key research problem in reinforcement learning (RL), and CURL, which uses contrastive learning to extract high-level features from raw pixels of individual video frames, is an efficient algorithm~\citep{srinivas2020curl}. We observe that consecutive video frames in a game are highly correlated but CURL deals with them independently. To further improve data efficiency, we propose a new algorithm, masked contrastive representation learning for RL, that takes the correlation among consecutive inputs into consideration. In addition to the CNN encoder and the policy network in CURL, our method introduces an auxiliary Transformer module to leverage the correlations among video frames. During training, we randomly mask the features of several frames, and use the CNN encoder and Transformer to reconstruct them based on the context frames. The CNN encoder and Transformer are jointly trained via contrastive learning where the reconstructed features should be similar to the ground-truth ones while dissimilar to others. During inference, the CNN encoder and the policy network are used to take actions, and the Transformer module is discarded. Our method achieves consistent improvements over CURL on $14$ out of $16$ environments from DMControl suite and $21$ out of $26$ environments from Atari 2600 Games. The code is available at https://github.com/teslacool/m-curl.

Xuerui Su, Yue Wang, Jinhua Zhu et al.

With the rapid development of Large Language Models (LLMs), numerous Reinforcement Learning from Human Feedback (RLHF) algorithms have been introduced to improve model safety and alignment with human preferences. These algorithms can be divided into two main frameworks based on whether they require an explicit reward (or value) function for training: actor-critic-based Proximal Policy Optimization (PPO) and alignment-based Direct Preference Optimization (DPO). The mismatch between DPO and PPO, such as DPO's use of a classification loss driven by human-preferred data, has raised confusion about whether DPO should be classified as a Reinforcement Learning (RL) algorithm. To address these ambiguities, we focus on three key aspects related to DPO, RL, and other RLHF algorithms: (1) the construction of the loss function; (2) the target distribution at which the algorithm converges; (3) the impact of key components within the loss function. Specifically, we first establish a unified framework named UDRRA connecting these algorithms based on the construction of their loss functions. Next, we uncover their target policy distributions within this framework. Finally, we investigate the critical components of DPO to understand their impact on the convergence rate. Our work provides a deeper understanding of the relationship between DPO, RL, and other RLHF algorithms, offering new insights for improving existing algorithms.

Jianfeng Cai, Jinhua Zhu, Ruopei Sun et al.

Reinforcement Learning from Human Feedback (RLHF) has achieved considerable success in aligning large language models (LLMs) by modeling human preferences with a learnable reward model and employing a reinforcement learning algorithm to maximize the reward model's scores. However, these reward models are susceptible to exploitation through various superficial confounding factors, with length bias emerging as a particularly significant concern. Moreover, while the pronounced impact of length bias on preference modeling suggests that LLMs possess an inherent sensitivity to length perception, our preliminary investigations reveal that fine-tuned LLMs consistently struggle to adhere to explicit length instructions. To address these two limitations, we propose a novel framework wherein the reward model explicitly differentiates between human semantic preferences and response length requirements. Specifically, we introduce a $\textbf{R}$esponse-$\textbf{c}$onditioned $\textbf{B}$radley-$\textbf{T}$erry (Rc-BT) model that enhances the model's capability in length bias mitigating and length instruction following, through training on our augmented dataset. Furthermore, we propose the Rc-RM and Rc-DPO algorithm to leverage the Rc-BT model for reward modeling and direct policy optimization (DPO) of LLMs, simultaneously mitigating length bias and promoting adherence to length instructions. Extensive experiments across various foundational models and datasets demonstrate the effectiveness and generalizability of our approach.

Kangwen Zhao, Jianfeng Cai, Jinhua Zhu et al.

Reinforcement Learning from Human Feedback relies on reward models to align large language models with human preferences. However, RLHF often suffers from reward hacking, wherein policy learning exploits flaws in the trained reward model to maximize reward scores without genuinely aligning with human preferences. A significant example of such reward hacking is length bias, where reward models usually favor longer responses irrespective of actual response quality. Previous works on length bias have notable limitations, these approaches either mitigate bias without characterizing the bias form, or simply assume a linear length-reward relation. To accurately model the intricate nature of length bias and facilitate more effective bias mitigation, we propose FiMi-RM (Bias Fitting to Mitigate Length Bias of Reward Model in RLHF), a framework that autonomously learns and corrects underlying bias patterns. Our approach consists of three stages: First, we train a standard reward model which inherently contains length bias. Next, we deploy a lightweight fitting model to explicitly capture the non-linear relation between length and reward. Finally, we incorporate this learned relation into the reward model to debias. Experimental results demonstrate that FiMi-RM achieves a more balanced length-reward distribution. Furthermore, when applied to alignment algorithms, our debiased reward model improves length-controlled win rate and reduces verbosity without compromising its performance.

Yutai Hou, Yingce Xia, Lijun Wu et al.

The Interaction between Drugs and Targets (DTI) in human body plays a crucial role in biomedical science and applications. As millions of papers come out every year in the biomedical domain, automatically discovering DTI knowledge from biomedical literature, which are usually triplets about drugs, targets and their interaction, becomes an urgent demand in the industry. Existing methods of discovering biological knowledge are mainly extractive approaches that often require detailed annotations (e.g., all mentions of biological entities, relations between every two entity mentions, etc.). However, it is difficult and costly to obtain sufficient annotations due to the requirement of expert knowledge from biomedical domains. To overcome these difficulties, we explore the first end-to-end solution for this task by using generative approaches. We regard the DTI triplets as a sequence and use a Transformer-based model to directly generate them without using the detailed annotations of entities and relations. Further, we propose a semi-supervised method, which leverages the aforementioned end-to-end model to filter unlabeled literature and label them. Experimental results show that our method significantly outperforms extractive baselines on DTI discovery. We also create a dataset, KD-DTI, to advance this task and will release it to the community.