Computational approaches to understanding protein aggregation in neurodegeneration

Abstract

The generation of toxic non-native protein conformers has emerged as a unifying thread among disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Atomic-level detail regarding dynamical changes that facilitate protein aggregation, as well as the structural features of large-scale ordered aggregates and soluble non-native oligomers, would contribute significantly to current understanding of these complex phenomena and offer potential strategies for inhibiting formation of cytotoxic species. However, experimental limitations often preclude the acquisition of high-resolution structural and mechanistic information for aggregating systems. Computational methods, particularly those combine both all-atom and coarse-grained simulations to cover a wide range of time and length scales, have thus emerged as crucial tools for investigating protein aggregation. Here we review the current state of computational methodology for the study of protein self-assembly, with a focus on the application of these methods toward understanding of protein aggregates in human neurodegenerative disorders.

An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

“…One of the most frequently used enhanced sampling technique is replica exchange MD (REMD), in which replicates of the system are simulated in parallel at different temperatures. More information on simulation approaches for studying protein aggregation can be found in recent reviews . This review primarily focuses on recent examples in which all‐atom molecular dynamics or REMD have been used to study the aggregation of Aβ, IAPP, or PrP.…”

“…More information on simulation approaches for studying protein aggregationc an be found in recent reviews. [151][152][153][154][155] This review primarily focuses on recente xamples in which all-atom molecular dynamics or REMD have been used to study the aggregation of Ab,I APP,o rP rP.H owever, other simulation approaches including Monte Carlo simulations and coarse-grained MD studies are also cited.…”

Molecular simulations of cellular processes

“…The most challenging is the difficulty to simulate large systems represented at full atomistic resolution for timescales longer than a few μs. Simulations of slower processes occurring in a cell, such as protein (mis)folding, macromolecular (dis)assembly, chromosome (de)condensation, and co-translational events, are, therefore, unfeasible with today's resources (Bhattacharya et al 2013;Phillip and Schreiber 2013;Redler et al 2014;Perilla et al 2015;Nilsson et al 2015;Korolev et al 2016;Zheng and Wen 2017), unless coarser-thanatomistic representations are employed (Takada 2012;Trovato and Tozzini 2012).…”

Chameleon behaviour of a-synuclein : brownian dynamics simulations of protein aggregation

“…Computer simulations present a powerful tool to investigate the various aggregates that a protein can form [162]. All-atom simulations provide insight into the precise aggregation mechanism for small peptides [12,109,115,187].…”

“…They are known to aggregate and form ordered fibrillar or amorphous structures [163] that may be toxic [30], leading to dopaminergic neural loss and both result in neurodegradation [105,150].…”