Xinshi Chen

Cong Liu, Milong Ren, Jiaqi Guan et al.

Recent advances in de novo protein binder design have enabled increasing experimental validation, yet reported in silico metrics remain difficult to interpret or compare across studies due to non-standardized evaluation protocols. We introduce ProtDBench, a standardized and throughput-aware evaluation framework for protein binder design. ProtDBench defines unified benchmark tasks, evaluation protocols, and success criteria, enabling systematic analysis of how evaluation design influences observed performance. Using a large wet-lab annotated dataset, we analyze commonly used structure prediction models as evaluation verifiers, revealing substantial verifier-dependent bias and limited agreement under identical filtering protocols. We then benchmark representative open-source generative binder design methods across ten diverse protein targets under a fixed evaluation protocol. Beyond per-sequence success rates, ProtDBench incorporates throughput-aware metrics based on a fixed 24-hour budget, as well as cluster-level success criteria to account for structural diversity. Together, these results expose systematic differences induced by filtering rules, success definitions, and throughput-aware evaluation between computational efficiency, success rate, and structural diversity. Overall, ProtDBench provides a fair and reproducible evaluation pipeline that supports systematic and controlled comparison of protein binder design methods under realistic evaluation settings.

Mengyang Liu, Shanchuan Li, Xinshi Chen et al.

Graph neural networks (GNNs) enable the analysis of graphs using deep learning, with promising results in capturing structured information in graphs. This paper focuses on creating a small graph to represent the original graph, so that GNNs trained on the size-reduced graph can make accurate predictions. We view the original graph as a distribution of receptive fields and aim to synthesize a small graph whose receptive fields share a similar distribution. Thus, we propose Graph Condesation via Receptive Field Distribution Matching (GCDM), which is accomplished by optimizing the synthetic graph through the use of a distribution matching loss quantified by maximum mean discrepancy (MMD). Additionally, we demonstrate that the synthetic graph generated by GCDM is highly generalizable to a variety of models in evaluation phase and that the condensing speed is significantly improved using this framework.

Harsh Shrivastava, Urszula Chajewska, Robin Abraham et al.

Probabilistic Graphical Models (PGMs) are generative models of complex systems. They rely on conditional independence assumptions between variables to learn sparse representations which can be visualized in a form of a graph. Such models are used for domain exploration and structure discovery in poorly understood domains. This work introduces a novel technique to perform sparse graph recovery by optimizing deep unrolled networks. Assuming that the input data $X\in\mathbb{R}^{M\times D}$ comes from an underlying multivariate Gaussian distribution, we apply a deep model on $X$ that outputs the precision matrix $\hatΘ$, which can also be interpreted as the adjacency matrix. Our model, uGLAD, builds upon and extends the state-of-the-art model GLAD to the unsupervised setting. The key benefits of our model are (1) uGLAD automatically optimizes sparsity-related regularization parameters leading to better performance than existing algorithms. (2) We introduce multi-task learning based `consensus' strategy for robust handling of missing data in an unsupervised setting. We evaluate model results on synthetic Gaussian data, non-Gaussian data generated from Gene Regulatory Networks, and present a case study in anaerobic digestion.

Chengyue Gong, Xinshi Chen, Yuxuan Zhang et al.

Lightweight inference is critical for biomolecular structure prediction and other downstream tasks, enabling efficient real-world deployment and inference-time scaling for large-scale applications. In this work, we address the challenge of balancing model efficiency and prediction accuracy by making several key modifications, 1) Multi-step AF3 sampler is replaced by a few-step ODE sampler, significantly reducing computational overhead for the diffusion module part during inference; 2) In the open-source Protenix framework, a subset of pairformer or diffusion transformer blocks doesn't make contributions to the final structure prediction, presenting opportunities for architectural pruning and lightweight redesign; 3) A model incorporating an ESM module is trained to substitute the conventional MSA module, reducing MSA preprocessing time. Building on these key insights, we present Protenix-Mini, a compact and optimized model designed for efficient protein structure prediction. This streamlined version incorporates a more efficient architectural design with a two-step Ordinary Differential Equation (ODE) sampling strategy. By eliminating redundant Transformer components and refining the sampling process, Protenix-Mini significantly reduces model complexity with slight accuracy drop. Evaluations on benchmark datasets demonstrate that it achieves high-fidelity predictions, with only a negligible 1 to 5 percent decrease in performance on benchmark datasets compared to its full-scale counterpart. This makes Protenix-Mini an ideal choice for applications where computational resources are limited but accurate structure prediction remains crucial.

Chaoran Cheng, Jiaqi Guan, Milong Ren et al.

We present A-CODE, a fully atomic unified one-stage protein co-design model that simultaneously refines discrete atom types and continuous atom coordinates. Unlike predominant two-stage methods that cascade structure design with amino acid-level sequence design, our approach is fully atomic within a unified multimodal diffusion framework, in which residue identities are inferred solely from atom-level predictions. Built upon the powerful all-atom architecture, A-CODE achieves superior designability for unconditional protein generation, outperforming all existing one-stage and two-stage design models. For binder design, A-CODE rivals and even outperforms existing state-of-the-art two-stage design models and, compared with the existing one-stage co-design model, achieves a drastic tenfold improvement in success rate on hard tasks. The inherent flexibility of our atomic formulation enables, for the first time, seamless adaptation to non-canonical amino acid (ncAA) modeling. Our fully atomic framework establishes a new, versatile foundation for all-atom generative modeling that can be naturally extended to complex biomolecular systems.

Xinshi Chen, Eric Chung

The thesis is about an application of the shape optimization to the morphological evolution of Golgi stack. Golgi stack consists of multiple layers of cisternae. It is an organelle in the biological cells. Inspired by the Helfrich Model \cite{Helfrich}, which is a model for vesicles typically applied to biological cells, a new model specially designed for Golgi stack is developed and then implemented using FEM in this thesis. In the Golgi model, each cisternae of the Golgi stack is viewed as a closed vesicle without topological changes, and our model is adaptable to both single-vesicle case and multiple-vesicle case. The main idea of the math model is to minimize the elastic energy(bending energy) of the vesicles, with some constraints designed regarding the biological properties of Golgi stack. With these constraints attached to the math model, we could extend this model to an obstacle-type problem. Hence, in the thesis, not only the simulations of Golgi stack are shown, but some interesting examples without biological meanings are also demonstrated. Also, as multiple cisternaes are considered as a whole, this is also a model handling multiple objects. A set of numerical examples is shown to compare with the observed shape of Golgi stack, so we can lay down some possible explanations to the morphological performance of trans-Golgi cisternae.

Bo Qiang, Chengyue Gong, Xinshi Chen et al.

Lightweight inference is critical for biomolecular structure prediction and downstream tasks, enabling efficient real-world deployment and inference-time scaling for large-scale applications. While AF3 and its variants (e.g., Protenix, Chai-1) have advanced structure prediction results, they suffer from critical limitations: high inference latency and cubic time complexity with respect to token count, both of which restrict scalability for large biomolecular complexes. To address the core challenge of balancing model efficiency and prediction accuracy, we introduce three key innovations: (1) compressing non-scalable operations to mitigate cubic time complexity, (2) removing redundant blocks across modules to reduce unnecessary overhead, and (3) adopting a few-step sampler for the atom diffusion module to accelerate inference. Building on these design principles, we develop Protenix-Mini+, a highly lightweight and scalable variant of the Protenix model. Within an acceptable range of performance degradation, it substantially improves computational efficiency. For example, in the case of low-homology single-chain proteins, Protenix-Mini+ experiences an intra-protein LDDT drop of approximately 3% relative to the full Protenix model -- an acceptable performance trade-off given its substantially 90%+ improved computational efficiency.

Xinshi Chen, Yan Zhu, Haowen Xu et al.

Dynamic graphs with ordered sequences of events between nodes are prevalent in real-world industrial applications such as e-commerce and social platforms. However, representation learning for dynamic graphs has posed great computational challenges due to the time and structure dependency and irregular nature of the data, preventing such models from being deployed to real-world applications. To tackle this challenge, we propose an efficient algorithm, Efficient Dynamic Graph lEarning (EDGE), which selectively expresses certain temporal dependency via training loss to improve the parallelism in computations. We show that EDGE can scale to dynamic graphs with millions of nodes and hundreds of millions of temporal events and achieve new state-of-the-art (SOTA) performance.

Xinshi Chen, Haoran Sun, Caleb Ellington et al.

We consider the problem of discovering $K$ related Gaussian directed acyclic graphs (DAGs), where the involved graph structures share a consistent causal order and sparse unions of supports. Under the multi-task learning setting, we propose a $l_1/l_2$-regularized maximum likelihood estimator (MLE) for learning $K$ linear structural equation models. We theoretically show that the joint estimator, by leveraging data across related tasks, can achieve a better sample complexity for recovering the causal order (or topological order) than separate estimations. Moreover, the joint estimator is able to recover non-identifiable DAGs, by estimating them together with some identifiable DAGs. Lastly, our analysis also shows the consistency of union support recovery of the structures. To allow practical implementation, we design a continuous optimization problem whose optimizer is the same as the joint estimator and can be approximated efficiently by an iterative algorithm. We validate the theoretical analysis and the effectiveness of the joint estimator in experiments.

Xinshi Chen, Yufei Zhang, Christoph Reisinger et al.

Recently, there has been a surge of interest in combining deep learning models with reasoning in order to handle more sophisticated learning tasks. In many cases, a reasoning task can be solved by an iterative algorithm. This algorithm is often unrolled, and used as a specialized layer in the deep architecture, which can be trained end-to-end with other neural components. Although such hybrid deep architectures have led to many empirical successes, the theoretical foundation of such architectures, especially the interplay between algorithm layers and other neural layers, remains largely unexplored. In this paper, we take an initial step towards an understanding of such hybrid deep architectures by showing that properties of the algorithm layers, such as convergence, stability, and sensitivity, are intimately related to the approximation and generalization abilities of the end-to-end model. Furthermore, our analysis matches closely our experimental observations under various conditions, suggesting that our theory can provide useful guidelines for designing deep architectures with reasoning layers.

Xinshi Chen, Hanjun Dai, Yu Li et al.

There is a recent surge of interest in designing deep architectures based on the update steps in traditional algorithms, or learning neural networks to improve and replace traditional algorithms. While traditional algorithms have certain stopping criteria for outputting results at different iterations, many algorithm-inspired deep models are restricted to a ``fixed-depth'' for all inputs. Similar to algorithms, the optimal depth of a deep architecture may be different for different input instances, either to avoid ``over-thinking'', or because we want to compute less for operations converged already. In this paper, we tackle this varying depth problem using a steerable architecture, where a feed-forward deep model and a variational stopping policy are learned together to sequentially determine the optimal number of layers for each input instance. Training such architecture is very challenging. We provide a variational Bayes perspective and design a novel and effective training procedure which decomposes the task into an oracle model learning stage and an imitation stage. Experimentally, we show that the learned deep model along with the stopping policy improves the performances on a diverse set of tasks, including learning sparse recovery, few-shot meta learning, and computer vision tasks.

Xinshi Chen, Yu Li, Ramzan Umarov et al.

In this paper, we propose an end-to-end deep learning model, called E2Efold, for RNA secondary structure prediction which can effectively take into account the inherent constraints in the problem. The key idea of E2Efold is to directly predict the RNA base-pairing matrix, and use an unrolled algorithm for constrained programming as the template for deep architectures to enforce constraints. With comprehensive experiments on benchmark datasets, we demonstrate the superior performance of E2Efold: it predicts significantly better structures compared to previous SOTA (especially for pseudoknotted structures), while being as efficient as the fastest algorithms in terms of inference time.

Yuyu Zhang, Xinshi Chen, Yuan Yang et al.

Markov Logic Networks (MLNs), which elegantly combine logic rules and probabilistic graphical models, can be used to address many knowledge graph problems. However, inference in MLN is computationally intensive, making the industrial-scale application of MLN very difficult. In recent years, graph neural networks (GNNs) have emerged as efficient and effective tools for large-scale graph problems. Nevertheless, GNNs do not explicitly incorporate prior logic rules into the models, and may require many labeled examples for a target task. In this paper, we explore the combination of MLNs and GNNs, and use graph neural networks for variational inference in MLN. We propose a GNN variant, named ExpressGNN, which strikes a nice balance between the representation power and the simplicity of the model. Our extensive experiments on several benchmark datasets demonstrate that ExpressGNN leads to effective and efficient probabilistic logic reasoning.

Xinshi Chen

To better understand and improve the behavior of neural networks, a recent line of works bridged the connection between ordinary differential equations (ODEs) and deep neural networks (DNNs). The connections are made in two folds: (1) View DNN as ODE discretization; (2) View the training of DNN as solving an optimal control problem. The former connection motivates people either to design neural architectures based on ODE discretization schemes or to replace DNN by a continuous model characterized by ODEs. Several works demonstrated distinct advantages of using a continuous model instead of traditional DNN in some specific applications. The latter connection is inspiring. Based on Pontryagin's maximum principle, which is popular in the optimal control literature, some developed new optimization methods for training neural networks and some developed algorithms to train the infinite-deep continuous model with low memory-cost. This paper is organized as follows: In Section 2, the relation between neural architecture and ODE discretization is introduced. Some architectures are not motivated by ODE, but they are later found to be associated with some specific discretization schemes. Some architectures are designed based on ODE discretization and expected to achieve some special properties. Section 3 formulates the optimization problem where a traditional neural network is replaced by a continuous model (ODE). The formulated optimization problem is an optimal control problem. Therefore, two different types of controls will also be discussed in this section. In Section 4, we will discuss how we can utilize the optimization methods that are popular in optimal control literature to help the training of machine learning problems. Finally, two applications of using a continuous model will be shown in Section 5 and 6 to demonstrate some of its advantages over traditional neural networks.

Yuyu Zhang, Xinshi Chen, Yuan Yang et al.

Effectively combining logic reasoning and probabilistic inference has been a long-standing goal of machine learning: the former has the ability to generalize with small training data, while the latter provides a principled framework for dealing with noisy data. However, existing methods for combining the best of both worlds are typically computationally intensive. In this paper, we focus on Markov Logic Networks and explore the use of graph neural networks (GNNs) for representing probabilistic logic inference. It is revealed from our analysis that the representation power of GNN alone is not enough for such a task. We instead propose a more expressive variant, called ExpressGNN, which can perform effective probabilistic logic inference while being able to scale to a large number of entities. We demonstrate by several benchmark datasets that ExpressGNN has the potential to advance probabilistic logic reasoning to the next stage.

Harsh Shrivastava, Xinshi Chen, Binghong Chen et al.

Recovering sparse conditional independence graphs from data is a fundamental problem in machine learning with wide applications. A popular formulation of the problem is an $\ell_1$ regularized maximum likelihood estimation. Many convex optimization algorithms have been designed to solve this formulation to recover the graph structure. Recently, there is a surge of interest to learn algorithms directly based on data, and in this case, learn to map empirical covariance to the sparse precision matrix. However, it is a challenging task in this case, since the symmetric positive definiteness (SPD) and sparsity of the matrix are not easy to enforce in learned algorithms, and a direct mapping from data to precision matrix may contain many parameters. We propose a deep learning architecture, GLAD, which uses an Alternating Minimization (AM) algorithm as our model inductive bias, and learns the model parameters via supervised learning. We show that GLAD learns a very compact and effective model for recovering sparse graphs from data.

Xinshi Chen, Hanjun Dai, Le Song

We present a particle flow realization of Bayes' rule, where an ODE-based neural operator is used to transport particles from a prior to its posterior after a new observation. We prove that such an ODE operator exists. Its neural parameterization can be trained in a meta-learning framework, allowing this operator to reason about the effect of an individual observation on the posterior, and thus generalize across different priors, observations and to sequential Bayesian inference. We demonstrated the generalization ability of our particle flow Bayes operator in several canonical and high dimensional examples.

Xinshi Chen, Shuang Li, Hui Li et al.

There are great interests as well as many challenges in applying reinforcement learning (RL) to recommendation systems. In this setting, an online user is the environment; neither the reward function nor the environment dynamics are clearly defined, making the application of RL challenging. In this paper, we propose a novel model-based reinforcement learning framework for recommendation systems, where we develop a generative adversarial network to imitate user behavior dynamics and learn her reward function. Using this user model as the simulation environment, we develop a novel Cascading DQN algorithm to obtain a combinatorial recommendation policy which can handle a large number of candidate items efficiently. In our experiments with real data, we show this generative adversarial user model can better explain user behavior than alternatives, and the RL policy based on this model can lead to a better long-term reward for the user and higher click rate for the system.