Bayesian optimization (BO) is a central tool for sample-efficient design, and latent-space Bayesian optimization (LSBO) extends it to structured objects such as molecules and proteins. In parallel, tabular foundation models such as TabPFN and TabICL now achieve state-of-the-art regression performance and are increasingly used as BO surrogates. Because their Bayesian behavior is induced by large synthetic pretraining collections, the composition of this pretraining distribution is crucial. LSBO creates a distinctive mismatch: the induced map from latent code to objective value differs markedly from the regression tasks used to train current in-context models. We address this mismatch by complementing the pretraining stage of tabular foundation model surrogates with synthetic optimization tasks defined on the latent space of a molecular VAE. The continued-pretraining objective features a regularizer that anchors the model to the original checkpoint, preserving its broad regression prior while avoiding overspecialization to the adaptation tasks. On held-out molecular optimization benchmarks, the resulting model achieves strong performance, supporting the relevance of LSBO-specific adaptation for in-context surrogates.
Generative models are increasingly central to many de novo discovery pipelines, in which designs are generated at scale and filtered through virtual screens to determine a set of candidates to experimentally validate. While Bayesian optimization (BO) is a natural fit for this setting, as it uses past evaluations to guide future proposals, the computational overhead required for its sequential decision-making becomes a bottleneck when virtual screens are relatively cheap. We make BO practical in this regime by exploiting the unique combination of a linear model constrained to a spherical domain where high-dimensional latents concentrate. We build off recent work justifying the use of linear surrogates, while deriving nearly closed-form solutions to the surrogate modelling and acquisition problems that exploit spherical symmetry. The result is at least a 100x speedup over state-of-the art baselines, with matching or improved performance across molecular and image generation benchmarks. Altogether, our method makes BO a practical drop-in for de novo pipelines where it was previously too slow to consider.
Practical molecular inverse design is rarely a one-shot generation problem; it often takes the form of closed-loop candidate-pool enrichment, where under a limited oracle budget the goal is to increase the fraction of generated molecules that match a desired property profile. Bayesian optimization (BO) offers a natural framework for this setting, yet standard Gaussian-process surrogates typically operate in compressed continuous embeddings, which discard the substructural and reference-similarity signals that chemists naturally use to decide where to look next. We propose BoMolLLM, a closed-loop framework in which the surrogate, rather than the generator, is treated as the locus of design choice, and instantiate it with a frozen large language model that reasons directly over the task instruction, SMILES-level optimization history, and oracle feedback in their native textual form. At each iteration, the surrogate returns a structured decision signal that selects informative reference molecules under an exploration and exploitation principle, optionally with a concise guidance sentence. This signal is converted into next-round conditioning text for a frozen molecular generator, yielding an inspectable optimization trace in natural language. Experiments on MolQA drug and material design tasks show that BoMolLLM improves over one-shot prompting, is competitive with or stronger than GP-based BO baselines, and reveals a domain-dependent interface: reference-only transfer works best for binary drug targets, while adding a concise surrogate summary is more beneficial for continuous material
Bayesian optimization (BO) relies on a surrogate model and an acquisition function, yet the most suitable choices vary across tasks and optimization stages. Automated Bayesian optimization (AutoBO) addresses this variability by adapting BO components online. However, existing AutoBO methods either adapt one component, leaving the other mismatched and creating a bottleneck, or jointly select surrogate--acquisition pairs under a shared criterion, overlooking their distinct roles: surrogate selection depends on predictive reliability, whereas acquisition adaptation should respond to campaign context.In this paper, we propose DASH, a Decoupled Adaptive Surrogate--Acquisition Harness for large-language- model (LLM)-enhanced AutoBO. DASH selects surrogates by predictive reliability, uncertainty calibration, and ranking consistency; its two-stage acquisition controller periodically reallocates quotas across acquisition functions, builds a BO shortlist accordingly, and delegates final selection to an LLM. DASH also incorporates an integrated harness, consisting of knowledge-guided warm start and structured memory, to ground optimization in domain knowledge and accumulated feedback. Across four chemical optimization tasks, DASH outperforms the best AutoBO baseline by 12.51% in trajectory-level Acceleration Factor and 5.00% in endpoint Enhancement Factor. Results remain strong across LLM backbones, and ablations verify the complementary contributions of all components. Full-table and behavioral contamination checks find no detectable evidence that direct benchmark memorization or source-cell leakage explains these gains.