Navigating Chemical Space: Multi-Level Bayesian Optimization with Hierarchical Coarse-Graining

Abstract: Molecular discovery within the vast chemical space remains a significant challenge due to the immense number of possible molecules and limited scalability of conventional screening methods. To approach chemical space exploration more effectively, we have developed an active learning-based method that uses transferable coarse-grained models to compress chemical space into varying levels of resolution. By using multiple representations of chemical space with different coarse-graining resolutions, we balance combinatorial complexity and chemical detail. To identify target compounds, we first transform the discrete molecular spaces into smooth latent representations. We then perform Bayesian optimization within these latent spaces, using molecular dynamics simulations to calculate target free energies of the coarse-grained compounds. This multi-level approach effectively balances exploration and exploitation at lower and higher resolutions, respectively. We demonstrate the effectiveness of our method by optimizing molecules to enhance phase separation in phospholipid bilayers. Our funnel-like strategy not only suggests optimal compounds but also provides insight into relevant neighborhoods in chemical space. We show how this neighborhood information from lower resolutions can guide the optimization at higher resolutions, thereby providing an efficient way to navigate large chemical spaces for free energy-based molecular optimization.