Prediction of NCα bond cleavage frequencies in electron capture dissociation of Trp-cage dications by force-field molecular dynamics simulations

Fragment ion abundances observed in electron capture dissociation (ECD) of dications of four stereoisomers (all-l, d-Tyr3, d-Gln5 and d-Leu7) of the Trp-cage protein correlated with the charge solvation patterns produced by molecular dynamics simulations (MDS) of the corresponding gas-phase structures. The degree of the correlation was however insufficient to distinguish the correct stereoisomers or make quantitative predictions. Much higher correlation was found between the ECD patterns and the frequencies of occurrence of neutral H-bonds to the carbonyls of the fragmenting amides. Based on this finding, a new ECD mechanism is suggested for NCα bond breakage, in which low-energy electrons are captured on a neutral hydrogen bond, with subsequent hydrogen atom transfer to the backbone carbonyl forming labile aminoketyl radical that rapidly fragments through α-cleavage. The neutral H-bonding model quantitatively predicted the ECD patterns of all four stereoisomers and correctly recognized them from the experimental data by comparing them to MDS results. The predictive power of the neutral H-bonding model may help in the future to solve gas-phase protein structures.