Molecular Dynamic Simulations Suggest That Metabolite-Induced Post-Translational Modifications Alter the Behavior of the Fibrinogen Coiled-Coil Domain.

Zofie Sovova,Jiri Suttnar,Jan E Dyr

doi:10.3390/metabo11050307

Zofie Sovova, Jiri Suttnar + Show 1 more

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https://doi.org/10.3390/metabo11050307

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Journal: Metabolites	Publication Date: May 11, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Institute of Haematology and Blood Transfusion

Abstract

Fibrinogen is an abundant blood plasma protein that, inter alia, participates in blood coagulation. It polymerizes to form a fibrin clot that is among the major components of the thrombus. Fibrinogen reactions with various reactive metabolites may induce post-translational modifications (PTMs) into the protein structure that affect the architecture and properties of fibrin clots. We reviewed the previous literature to find the positions of PTMs of fibrinogen. For 7 out of 307 reported PTMs, we used molecular dynamics simulations to characterize their effect on the behavior of the fibrinogen coiled-coil domain. Interactions of the γ-coil with adjacent chains give rise to π-helices in Aα and Bβ chains of even unmodified fibrinogen. The examined PTMs suppress fluctuations of the γ-coil, which may affect the fibrinolysis and stiffness of the fibrin fibers. Citrullination of AαR104 and oxidations of γP70 and γP76 to glutamic semialdehyde unfold the α-helical structure of Aα and Bβ chains. Oxidation of γM78 to methionine sulfoxide induces the formation of an α-helix in the γ-coil region. Our findings suggest that certain PTMs alter the protein secondary structure. Thus, the altered protein structure may indicate the presence of PTMs in the molecule and consequently of certain metabolites within the system.

Highlights

Variouschemical processes, including cellular respiration, cell replication and pathogen defense, are ongoing in all living organisms
The Aα chain is most prone to post-translational modifications (PTMs) (137 modified amino acids (AAs) at 109 sites), followed by the Bβ chain (105 AAs at 87 sites), and lastly, by the γ chain (65 AAs at 57 sites)
No PTM is reported in the αE variant of the Aα chain, which may be explained by a low abundance of this form (~2%), the eventual PTMs are below the detection limit of mass spectrometry

Summary

Introduction

Various (bio)chemical processes, including cellular respiration, cell replication and pathogen defense, are ongoing in all living organisms. Some of the metabolites are radicals (i.e., atoms or molecules owning at least one unpaired electron) or have unstable bonds, which makes them reactive. Under physiological conditions, these metabolites, known as reactive species (RS), participate in cell signaling, host defense and biosynthetic processes [1]. An excess of RS causes damage to other molecules. This is manifested by, for example, neurological and autoimmune diseases. A scarcity of RS disturbs the processes in which they are involved, which may be demonstrated by a decrease in antimicrobial defense, or low blood pressure [1,2]. The overabundance or deficiency of RS is referred to as oxidative stress [2]

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