(709h) Computational Modeling of Amyloid Aggregation Kinetics

Authors: 
Sharma, A., Georgia Institute of Technology
Chernoff, Y. O., Georgia Institute of Technology
Behrens, S. H., Georgia Institute of Technology
Bommarius, A. S., Georgia Institute of Technology
The aggregation of amyloidogenic proteins through cross �-sheet interactions depends upon two main factors: the primary sequence and environmental conditions such as presence of ions in solution1,2. The ordered fibrous aggregates formed as a result of this process are involved in a number of neurodegenerative diseases. The morphology of these aggregates is influenced by the aggregation kinetics and governs disease patterns in mammals and phenotypic differences in yeast.

The process of amyloid formation involves a two-step pattern of initial nucleation corresponding to a lag phase followed by a fiber elongation phase. This behavior has been modeled empirically using mathematical functions such as the logistic function, and other kinetic models, such as the Finke-Watzky (F-W) 2-step mechanism, which capture the near sigmoidal shape of the aggregation curve. However, experimental aggregation data does not always mirror the simple S-shape of a sigmoidal function. In this work we have developed a model for amyloid aggregation kinetics following a nucleation, elongation and fragmentation scheme. The effect of factors influencing aggregation kinetics is studied by changing parameters, such as fragmentation rate, initial concentrations of seeds, or critical nucleus size. Our results show that non-sigmoidal aggregation kinetics can result from varying some of the above mentioned parameters.

[1] Rubin, J., Khosravi, H., Bruce, K. L., Lydon, M. E., Behrens, S. H., Chernoff, Y. O. and Bommarius, A. S., 2013. Ion-specific effects on prion nucleation and strain formation. Journal of Biological Chemistry, 288(42), pp.30300-30308. doi: 10.1074/jbc.M113.467829

[2] Yeh, V., Broering, J. M., Romanyuk, A., Chen, B., Chernoff, Y. O. and Bommarius, A. S. (2010), The Hofmeister effect on amyloid formation using yeast prion protein. Protein Science, 19: 47â??56. doi: 10.1002/pro.281