Journal
JOURNAL OF CHEMICAL PHYSICS
Volume 152, Issue 4, Pages -Publisher
AMER INST PHYSICS
DOI: 10.1063/1.5133635
Keywords
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Funding
- Swiss National Science Foundation
- Peterhouse, Cambridge
- Schiff Foundation
- Ramon Jenkins Fellowship
- Sidney Sussex College Cambridge
- Swedish Research Council
- Wellcome Trust
- Cambridge Centre for Misfolding Diseases
- BBSRC
- Frances and Augustus Newman foundation
- European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) through the ERC grant PhysProt [337969]
- European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) through the ERC grant MAMBA [340890]
- European Research Council (ERC) [340890] Funding Source: European Research Council (ERC)
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The formation of amyloid fibrils from soluble peptide is a hallmark of many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Characterization of the microscopic reaction processes that underlie these phenomena have yielded insights into the progression of such diseases and may inform rational approaches for the design of drugs to halt them. Experimental evidence suggests that most of these reaction processes are intrinsically catalytic in nature and may display enzymelike saturation effects under conditions typical of biological systems, yet a unified modeling framework accounting for these saturation effects is still lacking. In this paper, we therefore present a universal kinetic model for biofilament formation in which every fundamental process in the reaction network can be catalytic. The single closed-form expression derived is capable of describing with high accuracy a wide range of mechanisms of biofilament formation and providing the first integrated rate law of a system in which multiple reaction processes are saturated. Moreover, its unprecedented mathematical simplicity permits us to very clearly interpret the effects of increasing saturation on the overall kinetics. The effectiveness of the model is illustrated by fitting it to the data of in vitro A beta 40 aggregation. Remarkably, we find that primary nucleation becomes saturated, demonstrating that it must be heterogeneous, occurring at interfaces and not in solution.
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