Can Semi-empirical Calculations Help Solve Mass Spectrometry Problems? Protonation Sites and Proton Affinities of Amino Acids

Authors

  • Dr. Paulo J. Amorim Madeira,

    Corresponding author
    1. iMed.UL-Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal)
    • iMed.UL-Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon (Portugal)
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  • Dr. Pedro D. Vaz,

    1. Centro de Química e Bioquímica, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa (Portugal)
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  • Dr. R. J. N. Bettencourt da Silva,

    1. Centro de Ciências Moleculares e Materiais, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa (Portugal)
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  • Prof. M. Helena Florêncio

    1. Centro de Química e Bioquímica, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa (Portugal)
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Abstract

Owing to the recent development of the PM6 and PM6-DH+ semi-empirical methodologies, which belong to the neglect of diatomic differential overlap (NDDO) family, it was decided to carry out a study to assess whether these inexpensive and fast methodologies could be used with confidence to help solve mass spectrometry problems. As such, a report on the feasibility of using semi-empirical calculations to identify probable protonation sites in amino acids is presented. The optimised geometries obtained by the semi-empirical calculations were compared to several structures reported in the literature (obtained through high-level theoretical calculations) and reasonable agreement was found. The proton affinities derived from semi-empirical calculations were also compared with experimental data and benchmarked as well with predicted values from the literature (also obtained through high-level theoretical calculations). Semi-empirical calculations accurately predicted the most probable protonation site for all amino acids considered; thus leading to results comparable to those obtained by high-level calculations at an extremely low computational cost. Regarding the proton affinity estimates, deviations from the available experimental values are greater for the semi-empirical proton affinities than for those observed for high-level calculations. A statistical analysis of the data, at a confidence level of 99 %, also showed that the semi-empirical proton affinities were different from experimental values and high-level proton affinities were equivalent to experimental values. Nevertheless, the overall correlation of the semi-empirical data with experimental values is, at least, satisfactory. We believe therefore that this paper shows that semi-empirical methodologies, which are fast and inexpensive, can indeed solve mass spectrometry problems, or at least, facilitate a quicker path to the solution.

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