Multiscale Models for Fibril Formation: Rare Events Methods, Microkinetic Models, and Population Balances

Abstract

Amyloid fibrils are thought to grow by a two-step dock-lock mechanism. However, previous simulations of fibril formation (i) overlook the bi-molecular nature of the docking step and obtain rates with first-order units, or (ii) superimpose the docked and locked states when computing the potential of mean force for association and thereby muddle the docking and locking steps. Here, we developed a simple microkinetic model with separate locking and docking steps and with the appropriate concentration dependences for each step. We constructed a simple model comprised of chiral dumbbells that retains qualitative aspects of fibril formation. We used rare events methods to predict separate docking and locking rate constants for the model. The rate constants were embedded in the microkinetic model, with the microkinetic model embedded in a population balance model for “bottom-up” multiscale fibril growth rate predictions. These were compared to “top-down” results using simulation data with the same model and multiscale framework to obtain maximum likelihood estimates of the separate lock and dock rate constants. We used the same procedures to extract separate docking and locking rate constants from experimental fibril growth data. Our multiscale strategy, embedding rate theories, and kinetic models in conservation laws should help to extract docking and locking rate constants from experimental data or long molecular simulations with correct units and without compromising the molecular description.

Multiscale Exploration of Concentration-Dependent Amyloid-β(16-21) Amyloid Nucleation

“…This challenge can be alleviated in part by enhanced sampling techniques, − ,− yielding certain insights into structural transition and intermediates of nucleation. − However, kinetic models of nucleation are still necessary for a comprehensive description of nucleation pathways and kinetics. It has been possible to derive such models based on atomistic simulations for amyloid elongation , but not for more complex processes like nucleation.…”