The residue-level free energy of opening (∆Gop) is the ultimate thermodynamic descriptor of localized protein stability, providing valuable information about the protein ensemble at physiologically relevant timescales and conditions. PFNet instantly determines ΔGop for arbitrarily large proteins and complexes from conventional peptide-level hydrogen exchange/mass spectrometry (HX/MS) datasets. It unlocks the full potential of HX/MS, democratizing the method and establishing quantitative, scalable and accessible analysis (https://github.com/glasgowlab/PFNet). Benchmark proteins in this dataset include AR61, the T4 lysozyme WT*, and GR3, the de novo designed mini-protein HHH_rd4_0557.