Background: Behavior of biomacromolecules is governed, inter alia, by their structure. Apart from widely used experimental methods for their characterization (X-ray diffraction, NMR, etc.), in silico methods become widely used in description of macromolecular since they are generally cheaper and can reveal features beyond the scope of experiment. Molecular dynamics (MD), Monte Carlo and numerous quantum calculations as well as molecular modelling and docking and various bioinformatics analyses are among the standard theoretical methods used in the field of life sciences to study molecules on atomistic scale.

Aims: The aim of this work is to propose techniques of molecular dynamics simulation and sequence analysis for coagulation studies and to demonstrate usage of these methods in characterization the effects of post-translational modifications (PTMs) on fibrinogen structure.

Methods: Molecular dynamics simulations of fibrinogen were performed in Gromacs software with Gromos 54a7 force field. PTMs were introduced into the truncated crystal structure 3GHG by Vienna-PTM 2.0 server. Sequence analysis was performed on sequences downloaded from NIH database.

Results: Molecular dynamics simulations revealed that PTMs can, but do not have to, influence secondary structure of fibrinogen and they can alter internal dynamic of the protein. On the example of MD simulation of pristine fibrinogen, we show that certain variations in secondary structure, those are not captured in the crystal structure, are native for the protein. We further revealed that various PTMs at the same position have different effect on fibrinogen behavior. Sequence analysis highlights the importance of proline in unfolded region of the γ chain (γY68 – γM78) within the coiled-coil domain of fibrinogen.

Conclusions: In silico methods captures characteristics and behavior of biomacromolecules that is unreachable by experiments. These methods can be used for understanding and interpretation of experimental results in the field of structural biology. (Funded by MH CR, grant number 00023736.)

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/in-silico-methods-of-structural-biology-for-studying-not-only-coagulation-proteins/