Mesoscale Modelling of Cytoplasmic Dynein using Fluctuating Finite Element Analysis

At the forefront of biological experimentation and simulation technology is the attempt to understand the biological mesoscale, the regime in which thermal fluctuations are still vital for function but atomic resolution may no longer be required. There is a
wealth of low-resolution biomolecular structural data of macromolecules available for study, and experimental developments are allowing these biomolecules to be visualised to near-atomic resolution without the need for crystallisation. It is clear that a new form of simulation is required to take advantage of this structural data in order to better understand the dynamics of proteins at the biological mesoscale, and their relationship
to dynamics at both the microscale and the macroscale.
The work presented in this thesis concerns the development of Fluctuating Finite Element Analysis (FFEA), a mesoscale simulation technique that treats globular macromolecules as visco-elastic continuum objects subject to an additional thermal stress, satisfying our definition of the mesoscale. I have further developed the constitutive continuum model to better represent biological macromolecules, and designed a new solution procedure in order to both increase the computational efficiency of the algorithm and to remove superfluous dynamical information. I also introduce a completely new kinetic framework that couples to the underlying simulation protocol, enabling us to simulate discrete biological events, such as conformational changes, within a continuous dynamical simulation.
I apply FFEA to the molecular motor cytoplasmic dynein, a mesoscopic system exhibiting dynamical features that are beyond the scope of standard molecular dynamics simulations, but well within the mesoscopic regime FFEA was designed for. I determine the physical parameters that an FFEA model of dynein requires for consistency with both experimental and high-resolution molecular dynamics simulations. Finally, I consider the diffusional properties of dynein with respect to its microtubule track, with the aim of understanding the potential mechanisms that enable the motor to be processive.