Coarse Grain Simulations Providing a Unifying Framework for Explaining Polyglutamine Aggregation Mechanism

Experiments and atomistic simulations show that homopolymeric polyglutamine forms heterogeneous distributions of collapsed, globular conformations in aqueous solutions. Atomistic simulations of monomer-dimer equilibria show that disordered polyglutamine globules associate to form disordered dimers, characterized by interactions between surface residues (the docked state) and interpenetrating chain molecules (the entangled state). Suppression of conformational fluctuations destabilizes the entangled state and inhibits dimerization. Similarly, naturally occurring flanking sequences from huntingtin destabilize the entangled state vis-a -vis the docked state.Our coarse-grained simulations help to understand the impact of the relative and absolute stabilities of entangled and docked states on the aggregation processes. A phenomenological pair potential is used to model the interplay between these states. Results from our coarse-grained Langevin dynamics simulations are summarized as follows: We define pairwise energy scale ΔU as (Ue - Ud) representing the energy gap between the entangled and docked states, reference state being the bistable situation of ΔU = 0 with Ud = Ue = 4kT, describing the association of homopolymeric polyglutamine molecules. Fixing Ue and increasing ΔU by increasing docked state stability, leads to an increase in the rate of monomer loss and formation of small number of large disordered clusters vis-a -vis the reference bistable state, describing modulation effects of the N-terminal flanking sequence from huntingtin. Conversely, increasing ΔU by destabilizing the entangled state decreases the rate of monomer loss vis-a-vis the reference bistable state accompanied by the formation of large, ordered clusters, describing the effects of C-terminal flanking sequences from huntingtin. Also, we show that electrostatic repulsions due to these residues retard the rate of monomer loss and large, linear, ordered clusters are formed. Our observations provide a unifying framework, capturing all known features of the early stages of aggregation in polyglutamine containing systems.