Modeling and simulation of fibrinogen and its adsorption behavior

In this thesis different approaches for the modeling and simulation of the blood protein fibrinogen are presented. The approaches are meant to systematically connect the multiple time and length scales involved in the dynamics of fibrinogen in solution and at inorganic surfaces. The first part of the thesis will cover simulations of fibrinogen on an all atom level. Simulations of the fibrinogen protomer and dimer are performed in explicit solvent to characterize the dynamics of fibrinogen in solution. These simulations reveal an unexpectedly large and fast bending motion that is facilitated by molecular hinges located in the coiled-coil region of fibrinogen. This behavior is characterized by a bending and a dihedral angle and the distribution of these angles is measured. As a consequence of the atomistic detail of the simulations it is possible to illuminate small scale behavior in the binding pockets of fibrinogen that hints at a previously unknown allosteric effect. In a second step atomistic simulations of the fibrinogen protomer are performed at graphite and mica surfaces to investigate initial adsorption stages. These simulations highlight the different adsorption mechanisms at the hydrophobic graphite surface and the charged, hydrophilic mica surface. It is found that the initial adsorption happens in a preferred orientation on mica. Many effects of practical interest involve aggregates of many fibrinogen molecules. To investigate such systems, time and length scales need to be simulated that are not attainable in atomistic simulations. It is therefore necessary to develop lower resolution models of fibrinogen. This is done in the second part of the thesis. First a systematically coarse grained model is derived and parametrized based on the atomistic simulations of the first part. In this model the fibrinogen molecule is represented by 45 beads instead of nearly 31,000 atoms. The intra-molecular interactions of the beads are modeled as a heterogeneous elastic network while inter-molecular interactions are assumed to be a combination of electrostatic and van der Waals interaction. A method is presented that determines the charges assigned to beads by matching the electrostatic potential in the atomistic simulation. Lastly a phenomenological model is developed that represents fibrinogen by five beads connected by rigid rods with two hinges. This model only captures the large scale dynamics in the atomistic simulations but can shed light on experimental observations of fibrinogen conformations at inorganic surfaces.