Exploring interactions of rod-like biological macromolecules through experimental and computational methods

The ability to solve the dynamics of biological macromolecules using computer simulation has been established as an essential tool of the biological sciences for over four decades. The most common technique is that of atomistic molecular dynamics, whereby every atom in a molecule is explicitly represented as a sphere of charge, and their trajectories are computed from interatomic potentials. Simulating the dynamics of particularly large and complex macromolecules containing millions of atoms or more remains computationally demanding, despite the critical importance of understanding such systems for addressing many research questions in molecular biology. Coarse-grained molecular simulations address this by abstracting away atomic detail, in order to reduce the computational power required to capture larger length and time scales. Elastic rod models are a particular type of coarse-grained representation optimised to calculate the deformation of long and thin objects, which are a common occurrence throughout biology. The KirchhOff Biological Rod Algorithm (KOBRA) is one such model that was developed recently, however, it does not capture any kind of intermolecular interactions, thus limiting its application to systems where macromolecules are unlikely to come into contact with each other. The work presented in this thesis concerns the continued development of the KOBRA simulation software, with a particular focus on the algorithms for repulsive steric interactions and attractive van der Waals forces. Fibrinogen, a large and fibrous blood protein, is used as an example macromolecule to place the results of the software development in a biological context. The computational performance of KOBRA is tested for systems in which hundreds of rods represent millions of atoms, the largest simulations to date with the software. Additional simulations of fibrin protofibrils, assembled from interacting fibrinogen rods, are also presented. Wet lab experiments are also presented that analyse the in-vitro mechanical response of fibrinogen to flow using a fluorescent labelling assay.