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Title: Modelling the evolution of biological complexity with a two-dimensional lattice self-assembly process
Author: Leonard, Alexander
ISNI:       0000 0004 9359 7757
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Self-assembling systems are prevalent across numerous scales of nature, lying at the heart of diverse physical and biological phenomena. Individual protein subunits self-assembling into complexes is often a vital first step of biological processes. Errors during protein assembly, due to mutations or misfolds, can have devastating effects and are responsible for an assortment of protein diseases, known as proteopathies. With proteins exhibiting endless layers of complexity, building any all-encompassing model is unrealistic. Coarse-grained models, despite not faithfully capturing every detail of the original system, have massive potential to assist understanding complex phenomenon. A principal actor in self-assembly is the binding interactions between subunits, and so geometric constraints, polarity, kinetic forces, etc. can often be marginalised. This work explores how self-assembly and its outcomes are inextricably tied to the involved interactions through the use of a two-dimensional lattice polyomino model. %Armed with this tractable model, we can probe how dynamics acting on evolution are reflected in interaction properties. First, this thesis addresses how the interaction characteristics of self-assembly building blocks determine what structures they form. Specifically, if the same structures are consistently produced and remain finite in size. Assembly graphs store subunit interaction information and are used in classifying these two properties, the determinism and boundedness respectively. Arbitrary sets of building blocks are classified without the costly overhead of repeated stochastic assembling, improving both the analysis speed and accuracy. Furthermore, assembly graphs naturally integrate combinatorial and graph techniques, enabling a wider range of future polyomino studies. The second part narrows in on implications of nondeterministic assembly on interaction strength evolution. Generalising subunit binding sites with mutable binary strings introduces such interaction strengths into the polyomino model. Deterministic assemblies obey analytic expectations. Conversely, interactions in nondeterministic assemblies rapidly diverge from equilibrium to minimise assembly inconsistency. Optimal interaction strengths during assembly are also reflected in evolution. Transitions between certain polyominoes are strongly forbidden when interaction strengths are misaligned. The third aspect focuses on genetic duplication, an evolutionary event observed in organisms across all taxa. Through polyomino evolutions, a duplication-heteromerisation pathway emerges as an efficient process. This pathway exploits the advantages of both self-interactions and pairwise-interactions, and accelerates evolution by avoiding complexity bottlenecks. Several simulation predictions are successfully validated against a large data set of protein complexes. These results focus on coarse-grained models rather than quantified biological insight. Despite this, they reinforce existing observations of protein complexes, as well as posing several new mechanisms for the evolution of biological complexity.
Supervisor: Ahnert, Sebastian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: biophysics ; self-assembly ; protein quaternary structure