Protein surface mapping, neurodegenerative diseases, bottom-up proteomics, MudPIT, isobaric 51 isotopologue, mass defect, quantitative mass spectrometry, structural proteomics, diffuse Lewy 52 body disease, conformational diagnostics, molecular diagnostics, conformational diagnostics. 53 Consistent with lysine being the most solvent accessible amino acid in proteins, initial 132 dimethylation labeled 337 out of 385 lysine sites (87.5 %) in > 95 % of protein or proteoform 133 molecules. The remaining 47 lysine sites were either completely inaccessible (13 sites) or 134 accessible in ≤ 95 % of protein molecules (34 sites, Extended data table 1). Several different 135 lysine sites of the metabolic enzyme Glyceraldehyde 3-phosphate dehydrogenase GAPDH were 136 quantified in the dataset and lysine sites GAPDH#K27, GAPDH#K55, and GAPDH#K139 were 137 measured as completely accessible in all GAPDH molecules. In contrast, lysine residue 138 GAPDH#K309 was accessible for chemical modification in < 75 % of GAPDH molecules 139