Simulation-Supervised Foundation Models for Retention Time Prediction in High-Performance Liquid Chromatography beyond Experimental Data Coverage

Abstract

Accurate prediction of high-performance liquid chromatography (HPLC) retention times (RTs) across diverse molecules and chromatographic methods remains challenging because experimental training data cover only a limited region of chemical and method spaces. Here, we develop FUSE-RT (Foundation model Unifying Simulation and Experimental supervision for Retention Time), a multitask foundation model that integrates RT data from 179 chromatographic methods and adapts to unseen molecules and methods using limited target-domain data. To extend transferability beyond experimental coverage, we introduce simulation-to-real (Sim2Real) transfer learning, in which molecular representations learned from large-scale computational data are transferred to experimental RT prediction. Specifically, we use PolyOmics, comprising 39 properties for approximately 21,400 molecules generated by molecular dynamics and density-functional theory calculations, as auxiliary supervision. We evaluate generalization under molecular, method, and joint molecular--method distribution shifts. Simulation-derived supervision substantially improves transfer beyond the experimental molecular domain, particularly under pronounced coverage gaps and few-shot adaptation. Moreover, RT-prediction error decreases systematically with increasing simulation-data size, following a significant power-law relationship. These results establish Sim2Real transfer as a scalable strategy for extending RT prediction beyond the finite coverage of experimental chromatographic data.