Molecular dynamics simulations of beta-2-glycoprotein 1 (β2GPI) reveal that post-translational modifications...

Beta-2-Glycoprotein I (β2GPI) is the main autoantigenic target of antiphospholipid syndrome (APS). β2GPI can adopt a number of structures; an extended J-shape, an O-shape and a transitional S-shape. It has also been shown previously that β2GPI can undergo a number of different post-translational modifications, altering its function and structure. It is unclear how the post translational modifications (PTMs) alter the progression through structures and if this alters the function of β2GPI. To study this we have chosen to use molecular dynamics simulations, providing fine atomistic details on the transition between structures, which can then be compared to findings published in the literature for validation. This study aimed to identify the potential effects of PTMs on the structure of β2GPI in-silico. Molecular simulations were carried out under standard physiological conditions (pH 7.4, 155 mM ionic strength, 1 bar pressure) for four models of β2GPI. These were the wild type, plasmin clipped (with terminal 8 amino acids removed), deglycosylated (with all four glycans removed) and reduced (with the terminal disulfide bond removed between C288-C326). Three repeats of 100 ns were carried out for each model. Plasmin cleavage and reduction generated structures absent from the wild type (WT). Plasmin cleavage generated a more compact structure with altered movement in Domain I (residues 1 to 60), whilst reduction produced unique elongated structures. These corroborated already published findings. Interestingly no simulation showed β2GPI circularise in these physiological simulations suggesting closing may not be an energetically favourable process. Molecular simulations of β2GPI identified structures only available to specific post translationally modified variants, and failed to show re-circularisation. Molecular simulations of β2GPI identified structures only available to specific post translationally modified variants, and failed to show re-circularisation.