RIDER: 3D RNA Inverse Design with Reinforcement Learning-Guided Diffusion

The inverse design of RNA three-dimensional (3D) structures is crucial for engineering functional RNAs in synthetic biology and therapeutics. While recent deep learning approaches have advanced this field, they are typically optimized and evaluated using native sequence recovery, which is a limited surrogate for structural fidelity, since different sequences can fold into similar 3D structures and high recovery does not necessarily indicate correct folding. To address this limitation, we propose RIDER, an RNA Inverse DEsign framework with Reinforcement learning that directly optimizes for 3D structural similarity. First, we develop and pre-train a GNN-based generative diffusion model conditioned on the target 3D structure, achieving a 9% improvement in native sequence recovery over state-of-the-art methods. Then, we fine-tune the model with an improved policy gradient algorithm using four task-specific reward functions based on 3D self-consistency metrics. Experimental results show that RIDER improves structural similarity by over 100% across all metrics and discovers designs that are distinct from native sequences.

Beyond Monotonicity: Revisiting Factorization Principles in Multi-Agent Q-Learning

Value decomposition is a central approach in multi-agent reinforcement learning (MARL), enabling centralized training with decentralized execution by factorizing the global value function into local values. To ensure individual-global-max (IGM) consistency, existing methods either enforce monotonicity constraints, which limit expressive power, or adopt softer surrogates at the cost of algorithmic complexity. In this work, we present a dynamical systems analysis of non-monotonic value decomposition, modeling learning dynamics as continuous-time gradient flow. We prove that, under approximately greedy exploration, all zero-loss equilibria violating IGM consistency are unstable saddle points, while only IGM-consistent solutions are stable attractors of the learning dynamics. Extensive experiments on both synthetic matrix games and challenging MARL benchmarks demonstrate that unconstrained, non-monotonic factorization reliably recovers IGM-optimal solutions and consistently outperforms monotonic baselines. Additionally, we investigate the influence of temporal-difference targets and exploration strategies, providing actionable insights for the design of future value-based MARL algorithms.