Physical Mechanisms of Collagen Self-Assembly: From Residue Interactions to Microfibril Structural Polymorphism

The structural protein collagen is often called the scaffold of multicellular life. From bone and cornea to the extracellular matrix and basement membranes of our vascular system, collagen is a key provider of structural support across a broad range of biological tissues.

The unique versatility of collagen as a structural protein is crucially aided by its ability to undergo self-assembly into intricate hierarchical structures. The hierarchical aggregates of collagen are characteristic in displaying various types of structural polymorphism. Yet, the biological functions of collagen are dependent on the structural features of its specific polymorphic aggregates.

The study of structural polymorphism of collagen constitutes the central topic of this thesis. Throughout the main chapters of this work, we aim to gain understanding of the physical interactions and mechanisms that govern the existence and competition between different polymorphic aggregates of collagen. To that end, we focus on the self-assembly of the smallest distinct unit in the collagen structural hierarchy - the microfibril.

Beginning with chapter 2, we show that the spatial organisation of interacting amino acids on the collagen molecular surface is chiral. We then demonstrate that this 3-dimensional spatial arrangement of amino acids is a crucial determinant of the structural features of collagen microfibrils as well as their polymorphisms. Continuing with chapter 3, we investigate the impact of ionic effects, namely pH and pKa on the aggregation of collagen microfibrils. We demonstrate how the aforementioned parameters as well as specific amino acid interactions stabilise different polymorphic aggregates of collagen under varying ionic conditions. Finally, in chapter 4, we study the polymorphisms of fibrous long-spacing (FLS) collagens. We determine the physical interactions that lead to their formation and predict the 3-dimensional molecular organisation within FLS collagen microfibrils.