Structure-based drug design (SBDD) aims to discover drug candidates by finding molecules (ligands) that bind tightly to a disease-related protein (targets), which is the primary approach to computer-aided drug discovery. Recently, applying deep generative models for three-dimensional (3D) molecular design conditioned on protein pockets to solve SBDD has attracted much attention, but their formulation as probabilistic modeling often leads to unsatisfactory optimization performance. On the other hand, traditional combinatorial optimization methods such as genetic algorithms (GA) have demonstrated state-of-the-art performance in various molecular optimization tasks. However, they do not utilize protein target structure to inform design steps but rely on a random-walk-like exploration, which leads to unstable performance and no knowledge transfer between different tasks despite the similar binding physics. To achieve a more stable and efficient SBDD, we propose Reinforced Genetic Algorithm (RGA) that uses neural models to prioritize the profitable design steps and suppress random-walk behavior. The neural models take the 3D structure of the targets and ligands as inputs and are pre-trained using native complex structures to utilize the knowledge of the shared binding physics from different targets and then fine-tuned during optimization. We conduct thorough empirical studies on optimizing binding affinity to various disease targets and show that RGA outperforms the baselines in terms of docking scores and is more robust to random initializations. The ablation study also indicates that the training on different targets helps improve performance by leveraging the shared underlying physics of the binding processes. The code is available at https://github.com/futianfan/reinforced-genetic-algorithm.

PROteolysis TArgeting Chimeras (PROTACs) are an emerging therapeutic modality for degrading a protein of interest (POI) by marking it for degradation by the proteasome. Recent developments in artificial intelligence (AI) suggest that deep generative models can assist with the de novo design of molecules with desired properties, and their application to PROTAC design remains largely unexplored. We show that a graph-based generative model can be used to propose novel PROTAC-like structures from empty graphs. Our model can be guided towards the generation of large molecules (30--140 heavy atoms) predicted to degrade a POI through policy-gradient reinforcement learning (RL). Rewards during RL are applied using a boosted tree surrogate model that predicts a molecule's degradation potential for each POI. Using this approach, we steer the generative model towards compounds with higher likelihoods of predicted degradation activity. Despite being trained on sparse public data, the generative model proposes molecules with substructures found in known degraders. After fine-tuning, predicted activity against a challenging POI increases from 50% to >80% with near-perfect chemical validity for sampled compounds, suggesting this is a promising approach for the optimization of large, PROTAC-like molecules for targeted protein degradation.

人工智能尚未彻底改变材料和分子的设计。在这种观点中，我们确定了四个障碍，阻碍了原子深度学习，分子科学和高性能计算的整合。我们概述了重点的研究努力，解决这些挑战所提供的机会。

分子和材料科学的深度学习受应用科学，人工智能和高性能计算之间缺乏融合的限制。关于培训数据量，模型架构的规模和复杂程度以及计算基础设施的规模的瓶颈是限制分子和材料深度学习缩放的关键因素。在这里，我们呈现$ \ texit {litmatter} $，轻量级框架用于缩放分子深度学习方法。我们在超过400个GPU上培训四个图形神经网络架构，并调查这些方法的缩放行为。根据模型架构，可以看到高达60美元的培训时间加速。经验神经缩放关系量化模型依赖性缩放，使能最优计算资源分配和可伸缩分子几何深度学习模型实现的识别。

Advancements in neural machinery have led to a wide range of algorithmic solutions for molecular property prediction. Two classes of models in particular have yielded promising results: neural networks applied to computed molecular fingerprints or expert-crafted descriptors, and graph convolutional neural networks that construct a learned molecular representation by operating on the graph structure of the molecule.However, recent literature has yet to clearly determine which of these two methods is superior when generalizing to new chemical space. Furthermore, prior research has

Despite their widespread adoption, neural conversation models have yet to exhibit natural chat capabilities with humans. In this research, we examine user utterances as causes and generated responses as effects, recognizing that changes in a cause should produce a different effect. To further explore this concept, we have compiled and expanded upon a new dataset called CausalDialogue through crowd-sourcing. This dataset includes multiple cause-effect pairs within a directed acyclic graph (DAG) structure. Our analysis reveals that traditional loss functions can struggle to effectively incorporate the DAG structure, leading us to propose a causality-enhanced method called Exponential Maximum Average Treatment Effect (ExMATE) to enhance the impact of causality at the utterance level in training neural conversation models. To evaluate the effectiveness of this approach, we have built a comprehensive benchmark using the CausalDialogue dataset leveraging large-scale pre-trained language models, and have assessed the results through both human and automatic evaluation metrics for coherence, diversity, and agility. Our findings show that current techniques are still unable to effectively address conversational DAGs, and that the ExMATE method can improve the diversity and agility of conventional loss functions while maintaining coherence.

We present a machine-learning framework to accurately characterize morphologies of Active Galactic Nucleus (AGN) host galaxies within $z<1$. We first use PSFGAN to decouple host galaxy light from the central point source, then we invoke the Galaxy Morphology Network (GaMorNet) to estimate whether the host galaxy is disk-dominated, bulge-dominated, or indeterminate. Using optical images from five bands of the HSC Wide Survey, we build models independently in three redshift bins: low $(0<z<0.25)$, medium $(0.25<z<0.5)$, and high $(0.5<z<1.0)$. By first training on a large number of simulated galaxies, then fine-tuning using far fewer classified real galaxies, our framework predicts the actual morphology for $\sim$ $60\%-70\%$ host galaxies from test sets, with a classification precision of $\sim$ $80\%-95\%$, depending on redshift bin. Specifically, our models achieve disk precision of $96\%/82\%/79\%$ and bulge precision of $90\%/90\%/80\%$ (for the 3 redshift bins), at thresholds corresponding to indeterminate fractions of $30\%/43\%/42\%$. The classification precision of our models has a noticeable dependency on host galaxy radius and magnitude. No strong dependency is observed on contrast ratio. Comparing classifications of real AGNs, our models agree well with traditional 2D fitting with GALFIT. The PSFGAN+GaMorNet framework does not depend on the choice of fitting functions or galaxy-related input parameters, runs orders of magnitude faster than GALFIT, and is easily generalizable via transfer learning, making it an ideal tool for studying AGN host galaxy morphology in forthcoming large imaging survey.

A prominent approach to solving combinatorial optimization problems on parallel hardware is Ising machines, i.e., hardware implementations of networks of interacting binary spin variables. Most Ising machines leverage second-order interactions although important classes of optimization problems, such as satisfiability problems, map more seamlessly to Ising networks with higher-order interactions. Here, we demonstrate that higher-order Ising machines can solve satisfiability problems more resource-efficiently in terms of the number of spin variables and their connections when compared to traditional second-order Ising machines. Further, our results show on a benchmark dataset of Boolean \textit{k}-satisfiability problems that higher-order Ising machines implemented with coupled oscillators rapidly find solutions that are better than second-order Ising machines, thus, improving the current state-of-the-art for Ising machines.

Semi-supervised learning methods can train high-accuracy machine learning models with a fraction of the labeled training samples required for traditional supervised learning. Such methods do not typically involve close review of the unlabeled training samples, making them tempting targets for data poisoning attacks. In this paper we investigate the vulnerabilities of semi-supervised learning methods to backdoor data poisoning attacks on the unlabeled samples. We show that simple poisoning attacks that influence the distribution of the poisoned samples' predicted labels are highly effective - achieving an average attack success rate as high as 96.9%. We introduce a generalized attack framework targeting semi-supervised learning methods to better understand and exploit their limitations and to motivate future defense strategies.

In this short technical note we propose a baseline for decision-aware learning for contextual linear optimization, which solves stochastic linear optimization when cost coefficients can be predicted based on context information. We propose a decision-aware version of predict-then-optimize. We reweigh the prediction error by the decision regret incurred by an (unweighted) pilot estimator of costs to obtain a decision-aware predictor, then optimize with cost predictions from the decision-aware predictor. This method can be motivated as a finite-difference, iterate-independent approximation of the gradients of previously proposed end-to-end learning algorithms; it is also consistent with previously suggested intuition for end-to-end learning. This baseline is computationally easy to implement with readily available reweighted prediction oracles and linear optimization, and can be implemented with convex optimization so long as the prediction error minimization is convex. Empirically, we demonstrate that this approach can lead to improvements over a "predict-then-optimize" framework for settings with misspecified models, and is competitive with other end-to-end approaches. Therefore, due to its simplicity and ease of use, we suggest it as a simple baseline for end-to-end and decision-aware learning.