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Atomistic simulations of the effects of polyglutamine chain length and solvent quality on conformational equilibria and spontaneous homodimerization.

ABSTRACT: Aggregation of expanded polyglutamine tracts is associated with nine different neurodegenerative diseases, including Huntington's disease. Experiments and computer simulations have demonstrated that monomeric forms of polyglutamine molecules sample heterogeneous sets of collapsed structures in water. The current work focuses on a mechanistic characterization of polyglutamine homodimerization as a function of chain length and temperature. These studies were carried out using molecular simulations based on a recently developed continuum solvation model that was designed for studying conformational and binding equilibria of intrinsically disordered molecules such as polyglutamine systems. The main results are as follows: Polyglutamine molecules form disordered, collapsed globules in aqueous solution. These molecules spontaneously associate at conditions approaching those of typical in vitro experiments for chains of length N>/=15. The spontaneity of these homotypic associations increases with increasing chain length and decreases with increasing temperature. Similar and generic driving forces govern both collapse and spontaneous homodimerization of polyglutamine in aqueous milieus. Collapse and dimerization maximize self-interactions and reduce the interface between polyglutamine molecules and the surrounding solvent. Other than these generic considerations, there do not appear to be any specific structural requirements for either chain collapse or chain dimerization; that is, both collapse and dimerization are nonspecific in that disordered globules form disordered dimers. In fact, it is shown that the driving force for intermolecular associations is governed by spontaneous conformational fluctuations within monomeric polyglutamine. These results suggest that polyglutamine aggregation is unlikely to follow a homogeneous nucleation mechanism with the monomer as the critical nucleus. Instead, the results support the formation of disordered, non-beta-sheet-like soluble molten oligomers as early intermediates--a proposal that is congruent with recent experimental data.

SUBMITTER: Vitalis A

PROVIDER: S-EPMC2847503 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Atomistic simulations of the effects of polyglutamine chain length and solvent quality on conformational equilibria and spontaneous homodimerization.

Vitalis Andreas A Wang Xiaoling X Pappu Rohit V RV

Journal of molecular biology 20080918 1

Aggregation of expanded polyglutamine tracts is associated with nine different neurodegenerative diseases, including Huntington's disease. Experiments and computer simulations have demonstrated that monomeric forms of polyglutamine molecules sample heterogeneous sets of collapsed structures in water. The current work focuses on a mechanistic characterization of polyglutamine homodimerization as a function of chain length and temperature. These studies were carried out using molecular simulations ...[more]

PMID: 18824003

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Project description:Adequate sampling of conformation space remains challenging in atomistic simulations, especially if the solvent is treated explicitly. Implicit-solvent simulations can speed up conformational sampling significantly. We compare the speed of conformational sampling between two commonly used methods of each class: the explicit-solvent particle mesh Ewald (PME) with TIP3P water model and a popular generalized Born (GB) implicit-solvent model, as implemented in the AMBER package. We systematically investigate small (dihedral angle flips in a protein), large (nucleosome tail collapse and DNA unwrapping), and mixed (folding of a miniprotein) conformational changes, with nominal simulation times ranging from nanoseconds to microseconds depending on system size. The speedups in conformational sampling for GB relative to PME simulations, are highly system- and problem-dependent. Where the simulation temperatures for PME and GB are the same, the corresponding speedups are approximately onefold (small conformational changes), between ?1- and ?100-fold (large changes), and approximately sevenfold (mixed case). The effects of temperature on speedup and free-energy landscapes, which may differ substantially between the solvent models, are discussed in detail for the case of miniprotein folding. In addition to speeding up conformational sampling, due to algorithmic differences, the implicit solvent model can be computationally faster for small systems or slower for large systems, depending on the number of solute and solvent atoms. For the conformational changes considered here, the combined speedups are approximately twofold, ?1- to 60-fold, and ?50-fold, respectively, in the low solvent viscosity regime afforded by the implicit solvent. For all the systems studied, 1) conformational sampling speedup increases as Langevin collision frequency (effective viscosity) decreases; and 2) conformational sampling speedup is mainly due to reduction in solvent viscosity rather than possible differences in free-energy landscapes between the solvent models.

Dataset Information

Atomistic simulations of the effects of polyglutamine chain length and solvent quality on conformational equilibria and spontaneous homodimerization.

Publications

Atomistic simulations of the effects of polyglutamine chain length and solvent quality on conformational equilibria and spontaneous homodimerization.

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