The effect of the Glu342Lys mutation in alpha1-antitrypsin on its structure, studied by molecular modelling medhods

The structure of native α1-antitrypsin, the most abundant protease inhibitor in human plasma, is characterised primarily by a reactive loop containing the centre of proteinase inhibition, and aβ-sheet composed of five strands. Mobility of the reactive loop is confined as a result of electrostatic interactions between side chains of Glu342 and Lys290, both lo­cated at the junction of the reactive loop and the β structure. The most common mutation in the protein, resulting in its inactivation, is Glu342->Lys, named the Z mutation. The main goal of this work was to investigate the influence of the Z mutation on the structure of α1-antitrypsin. Commonly used molecular modelling methods have been ap­plied in a comparative study of two protein models: the wild type and the Z mutant. The results indicate that the Z mutation introduces local instabilities in the region of the reactive loop. Moreover, even parts of the protein located far apart from the mutation re­gion are affected. The Z mutation causes a relative change in the total energy of about 3%. Relatively small root mean square differences between the optimised structures of the wild type and the Z mutant, together with detailed analysis of 'conformational searching' process, lead to the hypothesis that the Z mutation principally induces a change in the dy­namics of α1-antitrypsin.