Simulating oligomerization at experimental concentrations and long timescales: A Markov state model approach

Here, we present a novel computational approach for describing the formation of oligomeric assemblies at experimental concentrations and timescales. We propose an extension to the Markovian state model approach, where one includes low concentration oligomeric states analytically. This allows simulation on long timescales (seconds timescale) and at arbitrarily low concentrations (e.g., the micromolar concentrations found in experiments), while still using an all-atom model for protein and solvent. As a proof of concept, we apply this methodology to the oligomerization of an Aβ peptide fragment (Aβ_21-43). Aβ oligomers are now widely recognized as the primary neurotoxic structures leading to Alzheimer's disease. Our computational methods predict that Aβ trimers form at micromolar concentrations in 10ms, while tetramers form 1000 times more slowly. Moreover, the simulation results predict specific intermonomer contacts present in the oligomer ensemble as well as putative structures for small molecular weight oligomers. Based on our simulations and statistical models, we propose a novel mutation to stabilize the trimeric form of Aβ in an experimentally verifiable manner.