Reduction of Probabilistic Chemical Reaction Networks

The computability of real numbers and functions using Turing Machines has been a central area of theoretical computer science since the mid-20th century. In the late 20th century, it was shown that chemical reactions can serve as a basis for computation using the Chemical Reaction Network (CRN) model. Recent advances in computing real numbers using Deterministic Chemical Reaction Networks (DCRNs) have identified numerous classes of DCRN-computable real numbers. In parallel, the works of R. Landauer and C. H. Bennett, spanning the 1960s to the early 2000s, showed that reversible computing offers significant advantages over irreversible methods, particularly in energy efficiency, motivating extensive research on reversible computation. In this work, we investigate the computability of real numbers using Reversible Chemical Reaction Networks (RevCRNs). The paper has two primary contributions: (1) establishing relationships among CRN-computable real number classes including Lyapunov CRN ($\mathbb{R}_{LCRN}$), Real-Time CRN ($\mathbb{R}_{RTCRN}$), rational numbers ($\mathbb{Q}$), and RevCRNs ($\mathbb{R}_{RevCRN}$), with key results: (i) $\mathbb{Q}$ is a strict subset of $\mathbb{R}_{RevCRN}$; (ii) the set of positive algebraic numbers ($ALG$), $\mathbb{R}_{LCRN}$, and real numbers computable by 1-species RevCRN ($\mathbb{R}_{RevCRN}^{1s}$) are equal; (iii) $\mathbb{R}_{RTCRN}$ and $\mathbb{R}_{RevCRN}$ exhibit non-empty overlap; and (iv) the set of real numbers computable by detailed-balanced RevCRNs ($\mathbb{R}^{DetBal}_{RevCRN}$) is a subset of $ALG$; and (2) exploring the existence of a hierarchy within $\mathbb{R}_{RevCRN}$. Finally, we leave open the exact relationship between $\mathbb{R}_{RevCRN}$ and $\mathbb{R}_{RTCRN}$ while conjecturing a general hierarchy of RevCRN-computable reals.

Mapping a chemical reaction network, the graph of minima and transition states (TS) and the elementary reactions connecting them, is the natural language of chemistry, from catalysis to combustion to the origin of life. Constructing such a reaction network for a given chemistry has been impractical: it requires finding and characterizing tens of thousands of TS, a task for which traditional methods such as density functional theory (DFT) are typically prohibitively slow and require reactant and product as input. We introduce ReactionAtlas, which builds a reaction network $\textit{ab origine}$ from a handful of seed molecules and without hand-crafted rules. Specifically, our machine-learned generative model proposes reactions from kinetically sampled candidate compounds and a DFT-trained machine learned force field (MLFF) filters them to valid TS, the resulting products of which enter the search as new seeds. Starting from eight pre-biotic seeds (CH$_2$O, H$_2$O, OH$^-$, H$_3$O$^+$, CO$_2$, H$_2$CO$_3$, HCO$_3^-$, H), ReactionAtlas discovers $\sim$47,000 reactions among $\sim$12,000 compounds. The MLFF TSs match the PBE0 references within 0.5 Å RMSD in 85% of the cases and can be easily brought to the PBE0 level. Thus, ReactionAtlas maps small carbohydrate chemistry up to C$_4$H$_8$O$_4$ at unprecedented scale and accuracy, including charge and stereo information. It enables novel insights into many well-studied reaction paths, including the formose cycle, which we highlight for its centrality to the chemical origins of life. Notably, our framework also allows establishing alternative reaction pathways for formose chemistry.

Reaction yield prediction remains challenging because labeled data are scarce and reaction space is both combinatorially large and sparsely populated, limiting the generalization of existing reaction representations. String-, fingerprint-, and graph-based reaction encodings only partially capture chemical transformations, making accurate prediction difficult for reactions with complex substrates. We propose reaction contrastive learning foundation (RxnCLF), a self-supervised contrastive framework for reaction representation learning. RxnCLF is built on a condensed reaction graph (CRG) that unifies reactant and product information into a single graph, enabling the model to learn explicit and enriched transformation structure rather than disconnected graphs. Pretrained on 1.7 million Pistachio reactions, RxnCLF learns a compact and continuous latent space that captures both reaction-center features and broader side chain contexts, making it transformation-aware and chemically interpretable. Fine-tuned on multiple yield prediction benchmarks, including Buchwald-Hartwig, Pd-catalyzed BH coupling, and proprietary HTE C-N coupling and amide formation datasets, RxnCLF consistently outperforms graph and sequence-based baselines, improving R2 and achieving the best performance overall. Our results highlight the promise of CRG-based RxnCLF as a scalable reaction foundation model, with the potential to generalize across broader reaction spaces and support diverse downstream reaction informatics tasks, including regioselectivity prediction, enantioselectivity prediction, and reaction condition optimization.