Daily Papers

Traditional molecular string representations, such as SMILES, often pose challenges for AI-driven molecular design due to their non-sequential depiction of molecular substructures. To address this issue, we introduce Sequential Attachment-based Fragment Embedding (SAFE), a novel line notation for chemical structures. SAFE reimagines SMILES strings as an unordered sequence of interconnected fragment blocks while maintaining full compatibility with existing SMILES parsers. It streamlines complex generative tasks, including scaffold decoration, fragment linking, polymer generation, and scaffold hopping, while facilitating autoregressive generation for fragment-constrained design, thereby eliminating the need for intricate decoding or graph-based models. We demonstrate the effectiveness of SAFE by training an 87-million-parameter GPT2-like model on a dataset containing 1.1 billion SAFE representations. Through extensive experimentation, we show that our SAFE-GPT model exhibits versatile and robust optimization performance. SAFE opens up new avenues for the rapid exploration of chemical space under various constraints, promising breakthroughs in AI-driven molecular design.

Structure-Based molecule optimization (SBMO) aims to optimize molecules with both continuous coordinates and discrete types against protein targets. A promising direction is to exert gradient guidance on generative models given its remarkable success in images, but it is challenging to guide discrete data and risks inconsistencies between modalities. To this end, we leverage a continuous and differentiable space derived through Bayesian inference, presenting Molecule Joint Optimization (MolJO), the gradient-based SBMO framework that facilitates joint guidance signals across different modalities while preserving SE(3)-equivariance. We introduce a novel backward correction strategy that optimizes within a sliding window of the past histories, allowing for a seamless trade-off between explore-and-exploit during optimization. MolJO achieves state-of-the-art performance on CrossDocked2020 benchmark (Success Rate 51.3%, Vina Dock -9.05 and SA 0.78), more than 4x improvement in Success Rate compared to the gradient-based counterpart, and 2x "Me-Better" Ratio as much as 3D baselines. Furthermore, we extend MolJO to a wide range of optimization settings, including multi-objective optimization and challenging tasks in drug design such as R-group optimization and scaffold hopping, further underscoring its versatility. Code is available at https://github.com/AlgoMole/MolCRAFT.

Recently, 3D generative models have shown promising performances in structure-based drug design by learning to generate ligands given target binding sites. However, only modeling the target-ligand distribution can hardly fulfill one of the main goals in drug discovery -- designing novel ligands with desired properties, e.g., high binding affinity, easily synthesizable, etc. This challenge becomes particularly pronounced when the target-ligand pairs used for training do not align with these desired properties. Moreover, most existing methods aim at solving de novo design task, while many generative scenarios requiring flexible controllability, such as R-group optimization and scaffold hopping, have received little attention. In this work, we propose DecompOpt, a structure-based molecular optimization method based on a controllable and decomposed diffusion model. DecompOpt presents a new generation paradigm which combines optimization with conditional diffusion models to achieve desired properties while adhering to the molecular grammar. Additionally, DecompOpt offers a unified framework covering both de novo design and controllable generation. To achieve so, ligands are decomposed into substructures which allows fine-grained control and local optimization. Experiments show that DecompOpt can efficiently generate molecules with improved properties than strong de novo baselines, and demonstrate great potential in controllable generation tasks.

Modern coding scaffolds turn LLMs into capable software agents, but their ability to follow scaffold-specified instructions remains under-examined, especially when constraints are heterogeneous and persist across interactions. To fill this gap, we introduce OctoBench, which benchmarks scaffold-aware instruction following in repository-grounded agentic coding. OctoBench includes 34 environments and 217 tasks instantiated under three scaffold types, and is paired with 7,098 objective checklist items. To disentangle solving the task from following the rules, we provide an automated observation-and-scoring toolkit that captures full trajectories and performs fine-grained checks. Experiments on eight representative models reveal a systematic gap between task-solving and scaffold-aware compliance, underscoring the need for training and evaluation that explicitly targets heterogeneous instruction following. We release the benchmark to support reproducible benchmarking and to accelerate the development of more scaffold-aware coding agents.

Several recent advances in AI systems (e.g., Tree-of-Thoughts and Program-Aided Language Models) solve problems by providing a "scaffolding" program that structures multiple calls to language models to generate better outputs. A scaffolding program is written in a programming language such as Python. In this work, we use a language-model-infused scaffolding program to improve itself. We start with a seed "improver" that improves an input program according to a given utility function by querying a language model several times and returning the best solution. We then run this seed improver to improve itself. Across a small set of downstream tasks, the resulting improved improver generates programs with significantly better performance than its seed improver. Afterward, we analyze the variety of self-improvement strategies proposed by the language model, including beam search, genetic algorithms, and simulated annealing. Since the language models themselves are not altered, this is not full recursive self-improvement. Nonetheless, it demonstrates that a modern language model, GPT-4 in our proof-of-concept experiments, is capable of writing code that can call itself to improve itself. We critically consider concerns around the development of self-improving technologies and evaluate the frequency with which the generated code bypasses a sandbox.

We focus on agile, continuous, and terrain-adaptive jumping of quadrupedal robots in discontinuous terrains such as stairs and stepping stones. Unlike single-step jumping, continuous jumping requires accurately executing highly dynamic motions over long horizons, which is challenging for existing approaches. To accomplish this task, we design a hierarchical learning and control framework, which consists of a learned heightmap predictor for robust terrain perception, a reinforcement-learning-based centroidal-level motion policy for versatile and terrain-adaptive planning, and a low-level model-based leg controller for accurate motion tracking. In addition, we minimize the sim-to-real gap by accurately modeling the hardware characteristics. Our framework enables a Unitree Go1 robot to perform agile and continuous jumps on human-sized stairs and sparse stepping stones, for the first time to the best of our knowledge. In particular, the robot can cross two stair steps in each jump and completes a 3.5m long, 2.8m high, 14-step staircase in 4.5 seconds. Moreover, the same policy outperforms baselines in various other parkour tasks, such as jumping over single horizontal or vertical discontinuities. Experiment videos can be found at https://yxyang.github.io/jumping\_cod/.