Computational modelling of tropoelastin modifications and interactions

Despite their biological importance and prevalence, the elucidation of the structures and dynamics of highly flexible proteins have presented a profound challenge to the structural biological community. Improvements over the last decades in computational hardware and the accuracy of computational chemistry software have permitted the in-depth exploration of flexible proteins. Here, I delve into the molecular dynamics and mechanisms of tropoelastin - the building block of the elastin proteins - that are crucial to its functionality, and the interplay between primary sequence, local structure and global structure. I leverage the recently derived full-atomistic structure of tropoelastin through a series of computational molecular dynamics models to dissect three facets of tropoelastin's functionality in this thesis. Firstly, I examine the effect of natural modifications on the global and local structure of tropoelastin, and their implications for the self-assembly process through which elastin is formed. I find that the global structures deviate from the canonical wild type structure, indicating the formation of heterogeneous aggregates and cross-linking. The implied heterogeneity of these aggregates is further explored using dimers as representative nucleation events, where I examine the influence of physical forces and initial tropoelastin structures on early stage self-assembly. Dimers of tropoelastin result in surprisingly diverse associations, indicating that elastin assembly is not as homogeneous as previously thought. Finally, I probe the interaction between tropoelastin monomers and integrins, a class of cell receptors crucial for signalling and tissue integrity. I identify tropoelastin as a fuzzy binding protein which is capable of binding to integrins in a variety of conformations. Furthermore, I determine that tropoelastin exhibits preferential binding, which is dependent on the initial starting conformation