An operational perturbation proteomics-based virtual cell model.

Artificial intelligence-empowered virtual cell models represent an emerging approach for in silico drug discovery1-3, yet most existing approaches lack large-scale, time-resolved perturbation proteomics data and interpretable frameworks for predicting therapeutic responses. Here we generated more than 38 million temporal protein-abundance measurements from systematically perturbed breast cancer cell lines, and developed ProteinTalks, a virtual cell model. Central to ProteinTalks is the synergy of this large-scale dynamic proteomic resource and the model architecture, enabling a new pretraining framework that learns transferable dynamical latent representations from temporal proteome trajectories. By modelling how proteins respond conditionally to different perturbations, this approach enables the model to function as an operational tool for diverse drug discovery tasks: predicting drug efficacy and synergy, discovering new drug combinations, probing proteins associated with drug resistance, stratifying patient responses and prioritizing drug candidates for patient organoids. It also shows robust transferability, extending beyond cell lines to patient-derived organoids and clinical biopsies, generally achieving higher performance than the selected benchmark implementations under the evaluated protocols. Together, ProteinTalks shows how scalable pretraining of transferable dynamic representations enables operational, dynamics-aware, proteomics-based virtual cell models to advance in silico drug discovery.