Bridging length and time scales in filamentous protein self-assembly

 
Abstract:
 
Filamentous protein self-assembly is a process in which dispersed proteins assemble spontaneously to form ordered elongated structures. This phenomenon is an essential characteristic of life, but is also at the heart of pathologies of many types, including Parkinson’s and Alzheimer’s diseases. Moreover, filamentous growth is increasingly used in numerous nanotechnological applications. To exploit filamentous self-assembly for nanotechnology or curtail it for medical purposes it is necessary to quantify the fundamental principles that control the way dispersed molecules assemble into these ordered structures. The fundamental challenge in establishing such an understanding in a rigorous manner is the disparate nature of the spatial and temporal scales involved, which range from the molecular to the organism scale. In this talk, I demonstrate how this challenge can be partially addressed by bringing the power of physical methods to protein filament self-assembly to connect microscopic mechanisms with macroscopic observations of such phenomena. In a first part of the talk, I discuss a unified theory of the kinetics of filamentous protein assembly and show how these results reveal simple rate laws that provide the basis for interpreting experimental data in terms of specific mechanisms controlling the proliferation of fibrils. I also describe methods for understanding the factors that control the size of linear aggregating proteins, a crucial parameter that correlates with their neurotoxicity, and discuss how this framework allows us to study the modes of action through which molecular chaperones can suppress amyloid fibril formation. In a second part of the talk, I investigate filamentous growth reactions under confinement where statistical mechanical fluctuations play a significant role and illustrate how this strategy can be used to establish further mechanistic insights into protein filament formation. Finally, I explore the possibilities and performance limits of force generation and energy release by nanoscale self-assembling supra-molecular polymers.