Coarse-grained molecular dynamics simulations of fibrin polymerization: effects of thrombin concentration on fibrin clot structure (original) (raw)
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Coarse Grain Molecular Dynamics Simulation of Fibrin Polymerization
Studies suggests that patients with deep vein thrombosis and diabetes often have hyper coagulable blood plasma leading to higher chances of forming thromboembolisms by the rupture of blood clots, which may lead to stroke and death. Despite the advances in the field of blood clot formation and lysis research, the change in mechanical properties and its implication into the formation of thromboembolisms in platelet poor plasma is poorly understood. In this paper, we present a new computational method to simulate fibrin clot formation using molecular simulations. With an effective combination of reactive molecular dynamics concept and coarse graining principle, we have utilized the reactive coarse grain molecular dynamics to predict the complex network formation of fibrin clots and the branching of the fibrins. The heavy 340 kDa fibrinogen is converted into a simple spring-bead coarse grain system with 9 beads, and using our customized reactive potentials, we simulated the formation of the fibrin clot. Thus, formed fibrin clot agrees with the experimental results qualitatively, and to our best knowledge this is the first kind of molecular polymerization study of fibrin clot which can lead to improve our understanding about blood clot formation and its relationship with mechanical properties
Fibrin polymerization simulation using a reactive dissipative particle dynamics method
Biomechanics and Modeling in Mechanobiology
The study on the polymerization of fibrinogen molecules into fibrin monomers and eventually a stable, mechanically robust fibrin clot is a persistent and enduring topic in the field of thrombosis and hemostasis. Despite many research advances in fibrin polymerization, the change in the structure of fibrin clots and its influence on the formation of a fibrous protein network are still poorly understood. In this paper, we develop a new computational method to simulate fibrin clot polymerization using dissipative particle dynamics simulations. With an effective combination of reactive molecular dynamics formularies and many body dissipative particle dynamics principles, we constructed the reactive dissipative particle dynamics (RDPD) model to predict the complex network formation of fibrin clots and branching of the fibrin network. The 340 kDa fibrinogen molecule is converted into a spring-bead coarse-grain system with 11 beads using a topology representing network algorithm, and using RDPD, we simulated polymerization and formation of the fibrin clot. The final polymerized structure of the fibrin clot qualitatively agrees with experimental results from the literature, and to the best of our knowledge this is the first molecular-based study that simulates polymerization and structure of fibrin clots.
Multiscale Mechanics of Fibrin Polymer
Bulletin of the American …, 2009
Blood clots and thrombi consist primarily of fibrin, a branched, open mesh of polymeric fibers made of protein monomers, with a remarkable and unexplained extensibility and elasticity. Understanding the origin of fibrin mechanics may ultimately be significant for modulating ...
MODELING FIBRIN POLYMERIZATION IN BLOOD FLOW WITH DISCRETE-PARTICLES
2004
Excessive clotting can cause bleeding over a vast capillary areas contributing to stroke, heart attack or blindness. We study the mesoscopic dynamics of clotting by using a discrete-particle model. We assume that the plasma consists of fluid particles containing fibrin monomers, while the red blood cells and capillary walls are modeled using elastic mesh of "solid" particles. The fluid particles interact with each other with a short -ranged, repulsive dissipative force. The particles containing fibrin monomers have a dual character. The polymerization of fibrin monomers into hydrated fibrins is modeled by the change of the interactions between fluid particles from repulsive to attractive forces. This process occurs with a probability being an increasing function of a local density. We study the blood flow in microscopic capillary vessels about 100μm long and with diameters on order of 10μm. We show that the model of polymerization reflects well the role of fibrins in the c...
Recent advances in computational modeling of fibrin clot formation: A review
Computational Biology and Chemistry
The study of thrombosis is crucial to understand and develop new therapies for diseases like deep vein thrombosis, diabetes related strokes, pulmonary embolism etc. The last two decades have seen an exponential growth in studies related to the blood clot formation using computational tools and through experiments. Despite of this growth, the complete mechanism behind thrombus formation and hemostasis is not known yet. The computational models and methods used in this context are diversified into different spatiotemporal scales, yet there is no single model which can predict both physiological and mechanical properties of the blood clots. In this review, we will attempt to list out all major strategies attempted by researchers so far to model the blood clot formation using existing computational techniques. This review classifies them into continuum level, system level, discrete particles and multi-scale methods. We will also discuss the strength and weakness of various methods and possible future directions in which the computational blood clot research can thrive.
Proceedings of the National Academy of Sciences, 2000
A blood clot is a meshwork of fibrin fibers built up by the systematic assembly of fibrinogen molecules proteolyzed by thrombin. Here, we describe a model of how the assembly process occurs. Five kinds of interaction are explicitly defined, including two different knob-hole interactions, an end-to-end association between ␥-chains, a lateral association between ␥-chains, and a hypothetical lateral interaction between -chains. The last two of these interactions are responsible for protofibril association and are predicated on intermolecular packing arrangements observed in crystal structures of fibrin double-D fragments cocrystallized with synthetic peptides corresponding to the knobs exposed by the release of the fibrinopeptides A and B.
Mathematical model of fibrin polymerization
Blood clotting system (BCS) modelling is an important issue with a plenty of applications in medicine and biophysics. The BCS main function is to form a localized clot at the site of injury preventing blood loss. Mutual influence of fibrin clot consisting mainly of fibrin polymer gel and blood flow is an important factor for BCS to function properly. The process of fibrin polymer mesh formation has not adequately been described by current mathematical models. That is why it is not possible to define the borders of growing clot and model its interaction with a blood flow. This paper main goal is to propose physically well-founded mathematical model of fibrin polymerization and gelation. The proposed model defines the total length of fibrin polymer fibers in the unit volume, determines a position of the border between gel and liquid and allows to evaluate the permeability of growing gel. Without significant structural changes the proposed model could be modified to include the blood shear rate influence on the fibrin polymerization and gelation.
Atomic Structural Models of Fibrin Oligomers
Structure (London, England : 1993), 2018
The space-filling fibrin network is a major part of clots and thrombi formed in blood. Fibrin polymerization starts when fibrinogen, a plasma protein, is proteolytically converted to fibrin, which self-assembles to form double-stranded protofibrils. When reaching a critical length, these intermediate species aggregate laterally to transform into fibers arranged into branched fibrin network. We combined multiscale modeling in silico with atomic force microscopy (AFM) imaging to reconstruct complete atomic models of double-stranded fibrin protofibrils with γ-γ crosslinking, A:a and B:b knob-hole bonds, and αC regions-all important structural determinants not resolved crystallographically. Structures of fibrin oligomers and protofibrils containing up to 19 monomers were successfully validated by quantitative comparison with high-resolution AFM images. We characterized the protofibril twisting, bending, kinking, and reversibility of A:a knob-hole bonds, and calculated hydrodynamic param...
Multiscale Network Modeling of Fibrin Fibers and Fibrin Clots with Protofibril Binding Mechanics
Polymers
The multiscale mechanical behavior of individual fibrin fibers and fibrin clots wasmodeled by coupling atomistic simulation data and microscopic experimental data. We propose anew protofibril element composed of a nonlinear spring network, and constructed this based onmolecular simulations and atomic force microscopy results to simulate the force extension behaviorof fibrin fibers. This new network model also accounts for the complex interaction of protofibrilswith one another, the effects of the presence of a solvent, Coulombic attraction, and other bindingforces. The network model was formulated to simulate the force–extension mechanical behavior ofsingle fibrin fibers from atomic force microscopy experiments, and shows good agreement. Thevalidated fibrin fiber network model was then combined with a modified version of the Arruda–Boyce eight‐chain model to estimate the force extension behavior of the fibrin clot at the continuumlevel, which shows very good correlation. The results...