Defu Cao
Publications
Trustworthy Protein-Ligand Binding Affinity Prediction via Reliability-Aware Multi-Engine Fusion
Accurate protein-ligand binding affinity prediction is central to computational drug discovery, yet modern docking engines frequently disagree without indicating which prediction to trust. Consensus scoring and ensemble methods improve mean accuracy but treat all predictions identically without interpretable confidence measures or uncertainty decomposition, ignoring the chemical context of each protein-ligand pair. To address this limitation, we introduce RELIABLE-BA (RELIABiLity-aware Evidential fusion for Binding Affinity), an evidential framework for multi-engine binding affinity prediction. Our model comprises three steps: (1) modeling each engine as an evidential expert via Normal-Inverse-Gamma distributions, (2) scaling epistemic uncertainty through learned reliability from molecular context while preserving each expert's predictive mean, and (3) fusing experts through closed-form aggregation that captures both individual uncertainty and inter-engine disagreement. Experiments on the PDBBind and BDB2020+ benchmarks demonstrate competitive point prediction with substantially improved uncertainty calibration, and additional validation on the SARS-CoV-2 Mpro dataset and 5HT2A receptor demonstrates applicability to clinically relevant drug targets. Crucially, these uncertainty estimates enable reliable filtering of protein-ligand pairs, reducing prediction error by up to 25% when retaining only high-confidence pairs. To our knowledge, RELIABLE-BA is the first multi-engine binding affinity prediction framework to combine evidential fusion with context-dependent reliability, offering a principled path toward trustworthy AI-guided drug discovery. Our code is publicly available at https://github.com/yongchand/RELIABLE-BA.
Speaking Numbers to LLMs: Multi-Wavelet Number Embeddings for Time Series Forecasting
Large language models (LLMs) are attractive for context-aware time series forecasting because they can integrate heterogeneous textual signals, yet their discrete, language-oriented tokenization and embedding interfaces are misaligned with continuous numerical values, often harming numerical ordering and forecasting reliability. We propose TempoWave, a plug-and-play temporal wavelet digit interface that maps each scalar observation into digit-wise embeddings constructed from multi-wavelet, multi-scale coefficients. By directly overriding standard token representations, TempoWave seamlessly exposes both fine-grained local fluctuations and macro global structures in a transformer-compatible form, ensuring that precise numerical formatting, distinct digit identity, and robustness to common normalization operations are maintained throughout the LLM pipeline. Experiments across five context-enriched forecasting benchmarks demonstrate that TempoWave consistently improves LLM-based forecasters over standard numeric tokenization and alternative embedding interfaces, achieving a new state-of-the-art. These results highlight the numeric interface as a key bottleneck and suggest that principled multi-resolution embeddings can better couple LLMs' contextual reasoning with precise forecasting. Our code is available at https://github.com/DC-research/TempoWAVE and our model can be accessed at https://huggingface.co/Melady/TempoWAVE.
Adaptive Collaboration with Humans: Metacognitive Policy Optimization for Multi-Agent LLMs with Continual Learning
While scaling individual Large Language Models (LLMs) has delivered remarkable progress, the next frontier lies in scaling collaboration through multi-agent systems (MAS). However, purely autonomous MAS remain ''closed-world'' systems, constrained by the static knowledge horizon of pre-trained models. This limitation makes them brittle on tasks requiring knowledge beyond training data, often leading to collective failure under novel challenges. To address this, we propose the Human-In-the-Loop Multi-Agent Collaboration (HILA) framework, a principled paradigm for human--agent collaboration. HILA trains agents to learn a metacognitive policy that governs when to solve problems autonomously and when to defer to a human expert. To operationalize this policy, we introduce Dual-Loop Policy Optimization, which disentangles immediate decision-making from long-term capability growth. The inner loop applies Group Relative Policy Optimization (GRPO) with a cost-aware reward to optimize deferral decisions, while the outer loop implements continual learning, transforming expert feedback into high-quality supervised signals that strengthen the agent's reasoning ability. Experiments on challenging mathematical and problem-solving benchmarks show that HILA, equipped with Dual-Loop Policy Optimization, consistently outperforms advanced MAS, establishing a principled foundation for collaborative and continually improving agentic systems.
TemporalBench: A Benchmark for Evaluating LLM-Based Agents on Contextual and Event-Informed Time Series Tasks
It is unclear whether strong forecasting performance reflects genuine temporal understanding or the ability to reason under contextual and event-driven conditions. We introduce TemporalBench, a multi-domain benchmark designed to evaluate temporal reasoning behavior under progressively richer informational settings. TemporalBench adopts a four-tier task taxonomy that examines historical structure interpretation, context-free forecasting, contextual temporal reasoning, and event-conditioned prediction across four real-world domains: retail, healthcare, energy, and physical systems. By controlling access to future targets and contextual information, the benchmark enables a diagnostic analysis of whether models can correctly interpret temporal patterns, align them with external context, and adapt predictions when conditions change. Extensive baseline experiments show that strong numerical forecasting accuracy does not reliably translate into robust contextual or event-aware temporal reasoning; instead, existing agent frameworks exhibit fragmented strengths and systematic failure modes that remain largely hidden under forecasting-only benchmarks. The TemporalBench dataset is publicly available at https://huggingface.co/datasets/Melady/TemporalBench, and we additionally provide a public leaderboard at https://huggingface.co/spaces/Melady/TemporalBench_Leaderboard.