Porelike morphologies in amyloidogenic proteins

Matthew J. Voelker

doi:10.17918/etd-7570

Intrinsically disordered proteins (IDPs) have been linked to a variety of human diseases. The roles that IDPs play in physiological functions and disease pathology are frequently an enigma. Their disordered nature and structural complexity presents significant experimental and computational challenges, and makes IDPs difficult to study and characterize effectively. Soluble, low molecular weight (LMW) oligomers of the IDPs amyloid [beta]-protein (A[beta]) and alpha-synuclein ([alpha]S) have been hypothesized to be the primary neurotoxic agents in Alzheimer's Disease (AD) and Parkinson's Disease (PD) respectively, however their structure remains elusive. In this thesis, we take a varied computational approach in studies of A[beta] and [alpha]S oligomers in order to probe and elucidate their structure. A[beta] oligomers have been observed to impair cognition in live rats and to negatively affect memory by hindering long-term potentiation in the hippocampus. Of the two predominant A[beta] alloforms, A[beta]40 and A[beta]42, the latter is more strongly associated with AD. Here, we structurally characterize A[beta]40 and A[beta]42 monomers through pentamers via a multi-scale computational approach, wherein conformations derived by discrete molecular dynamics combined with an implicit-solvent intermediate-resolution protein model and amino acid-specific interactions (DMD4B-HYDRA) were converted into all-atom conformations and subjected to explicit-solvent MD. Unlike the initial DMD4B-HYDRA conformations, fully atomistic A[beta]40 and A[beta]42 trimers, tetramers, and pentamers form water-permeable pores, whereby the tendency for pore formation sharply increases with oligomer order and is the highest for A[beta]42 pentamers. Our findings reveal an extraordinary ability of A[beta] oligomers to form pores in pure water prior to their insertion into a membrane. PD is characterized in part by the cerebral accumulation of alpha-synuclein, a 140 amino acids-long protein produced naturally in the body, into abnormal intracellular protein deposits in the brain. Soluble [alpha]S oligomers in particular have been shown to be toxic to neuronal cell cultures in vitro. We here characterize the structure of [alpha]S oligomers computationally using the DMD4B-HYDRA approach. We vary the implicit-solvent parameter corresponding to the strength of electrostatic interactions (E_[CH]) to fine tune the solvent conditions in order to obtain an [alpha]S oligomer distribution consistent with experimental data. The population of [alpha]S oligomers is characterized by a monotonically decreasing propensity of monomers through septamers followed by an increase in octamers. We observe that [alpha]S forms water-permeable pores in all assembly states, with a propensity for pore formation that increases with oligomer order. Previous studies have reported that both A[beta] and [alpha]S oligomers form ion channels when embedded into a cellular membrane, which causes an abnormal ion flux and eventually leads to cell death. These observations form a leading theory for the mechanism behind the cytotoxicity associated with AD and PD, known as the ion channel hypothesis. The observations of porelike morphologies in our studies of LMW oligomers of A[beta] and [alpha]S, which form in the absence of a membrane and increase in propensity with oligomer order, provides important insights and further support to the ion channel hypothesis of AD and PD.

Porelike morphologies in amyloidogenic proteins

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Porelike morphologies in amyloidogenic proteins

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