A Coarse-Grained Model for Polyglutamine Aggregation Modulated by Amphipathic Flanking Sequences

Abstract

The aggregation of proteins with expanded polyglutamine (polyQ) tracts is directly relevant to the formation of neuronal intranuclear inclusions in Huntington's disease. In vitro studies have uncovered the effects of flanking sequences as modulators of the driving forces and mechanisms of polyQ aggregation in sequence segments associated with HD. Specifically, a seventeen-residue amphipathic stretch (N17) that is directly N-terminal to the polyQ tract in huntingtin decreases the overall solubility, destabilizes nonfibrillar aggregates, and accelerates fibril formation. Published results from atomistic simulations showed that the N17 module reduces the frequency of intermolecular association. Our reanalysis of these simulation results demonstrates that the N17 module also reduces interchain entanglements between polyQ domains. These two effects, which are observed on the smallest lengthscales, are incorporated into phenomenological pair potentials and used in coarse-grained Brownian dynamics simulations to investigate their impact on large-scale aggregation. We analyze the results from Brownian dynamics simulations using the framework of diffusion-limited cluster aggregation. When entanglements prevail, which is true in the absence of N17, small spherical clusters and large linear aggregates form on distinct timescales, in accord with in vitro experiments. Conversely, when entanglements are quenched and a barrier to intermolecular associations is introduced, both of which are attributable to N17, the timescales for forming small species and large linear aggregates become similar. Therefore, the combination of a reduction of interchain entanglements through homopolymeric polyQ and barriers to intermolecular associations appears to be sufficient for providing a minimalist phenomenological rationalization of in vitro observations regarding the effects of N17 on polyQ aggregation.

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

“…6,168 Thus, the current data are consistent with the idea that prion-like domains form transient oligomeric assemblies. These assemblies could arise either from weak multivalent interactions as proposed most clearly for polyglutamine domains 148,195,196 or by reversible stacking of monomers into reversible oligomeric assemblies mediated by transient b-sheet interactions. 8 …”

Molecular simulations of cellular processes

“…The Lennard-Jones potential is a simple functional form, in which the single well describes an isotropic, short-ranged attraction. More complex functional forms, such as isotropic multiwell potentials, have been used to model desolvation between amino acids during protein folding, allosteric transitions, DNA supercoiling, and protein aggregation (Okazaki et al 2006;Chu and Voth 2007;Trovato and Tozzini 2008;Trovato et al 2013;Ruff et al 2014). Nonisotropic potentials have been used to describe the interactions between crystallins mediated by patches of amino acids (Staneva and Frenkel 2015;Bucciarelli et al 2016).…”

Computational Approaches to Understanding the Biological Behaviour of Intrinsically Disordered Proteins

“…A coarse grained potential is essentially a description of interactions where the degrees of freedom of individual atoms are not considered independently, but a chemical group is described as a spherical mass with an overall charge. Coarsegrained simulations use longer time steps and are capable of sampling systems of much larger dimensions than atomistic force fields, and are therefore useful in investigating higher ordered growth in IDP aggregation [75][76][77][78][79][80][81][82] . A recent work by Kurcinski et al 83 utilized a coarse-grained approach to characterize the various modes of complex formation and interactions of the IDP, phosphorylated kinase-inducible domain (pKID) and its interacting domain KIX.…”