Fitting in and Avoiding the Path of Least Resistance

Reductionist models have always been a central element of the physicist's toolkit. But, this approach creates a culture clash at the interface of physics and biology where small details are responsible for major differences in form and function. In this talk I will describe the approach used in my group to bridge these differences. As an example of this approach, I will describe our recent work on the nucleation of amyloid fibrils.

Amyloids are protein aggregates responsible for neurodegenerative disorders like Alzheimer's and prion diseases. Despite the one-dimensional appearance of these aggregates, they show nucleation limited kinetics as expected for bulk phase transitions in higher dimensions. I will present an exactly solvable model showing that the nucleation lag time arises from both the translational and conformational entropy of the molecules. Interestingly, we find that the polymer dynamics makes nucleation extremely unlikely along the lowest free energy pathway. I will conclude by showing how these simple models can be used to extend the accessible timescales of high resolution simulations by many orders of magnitude.