Uncertainty-aware reinforcement learning for chemical language models

Abstract

Reinforcement Learning (RL) has become a powerful paradigm for de novo molecular design, enabling Chemical Language Models (CLMs) to navigate and explore the chemical space while optimizing specific desired properties. However, the existing RL frameworks treat all scoring functions as deterministic oracles, neglecting the inherent uncertainty attached to the predictions of the different molecular properties. This can lead to the exploration of highly-uncertain regions of the chemical space, focusing on the generation of highly scored molecules which are poorly supported by the training data. This can destabilize the optimization process, yielding predictions that are far from their true values. We propose and compare two complementary ways of incorporating predictive uncertainty into RL. In the first one, uncertainty is treated as an additional optimization objective and incorporated along with the rest of the scoring functions, allowing the policy to trade off exploitation against reliability. Secondly, uncertainty is used to modulate policy updates, reducing the influence of molecules whose properties lie far outside the scoring function confidence domain. Both approaches were evaluated across three different settings: (i) a controlled model system, in which the prediction error is modeled as a Gaussian distribution, with a variance proportional to the distance to the training data; and two real-world tasks, making use of (ii) ChemProp models and (iii) a Conformal Prediction wrapper applied to a Random forest classifier. We show that uncertainty-aware RL enables CLMs to explore chemical space more robustly by favoring lower-uncertainty regions. This leads to more reliable hit discovery without compromising molecular score, increasing the true hit rate by 0.25 (from 0.5 to 0.75), and nearly doubling the total number of true hits.