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

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