Molecular Neuroscience - overview
Characterization of Alzheimer's Protective and Causative Mutations
The aggregation of amyloid-beta (Aβ) peptides plays a crucial role in the etiology of Alzheimer’s disease (AD). Recently, it has been reported that an A2T mutation in Aβ can protect from AD. Interestingly, an A2V mutation has been also found to offer protection against AD in the heterozygous state. We have characterized the conformational landscapes of the WT, A2V, and A2T Aβ1-42 variant monomers using extensive atomistic molecular dynamics (MD) simulations. An enhanced double hairpin population in A2V was observed due to hydrophobic clustering. In contrast, the A2T mutation induces unusual long-range electrostatic interactions, resulting in a “unique” population. These structural insights obtained from MD allow understanding of the differential aggregation, oligomer morphology, and long-term potentiation (LTP) inhibition of the variants observed in the experiments. Interestingly, the protective A2T variant showed a reduced LTP inhibition effect in rat hippocampal CA1 neurons. In summary, these results suggest that conformational differences between variants underlie enhanced and reduced causation of AD. Collaborator: Georges Belfort (RPI).
Mechanism of Molecular Interference with Amyloid-beta Aggregation
Both chaperone (e.g. human alphaB crystallin) and non-chaperone (human lysozyme) proteins are found to interfere with amyloid-beta aggregation and related toxicity, suggesting a protective role of those proteins in Alzheimer's disease. Thus, knowledge of the detailed mechanism by which human aB crystallin and human lysozyme inhibit Aβ peptide aggregation is crucial for designing treatment for Alzheimer’s disease. Thus,unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17-42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during very early stage aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows stronger binding with Aβ peptide monomers. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human aB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors. Collaborator: Georges Belfort (RPI) & Sally Temple (NSCI).
Molecular Origin of Huntinton's Disease
Huntington’s disease (HD) is a dominantly transmitted neurodegenerative disorder that typically strikes in midlife and is accompanied by steady decline in the basal ganglia and cerebral cortex regions of human brain. Characteristic symptoms of this "trinucleotide repeat" disorder include involuntary movements, cognitive deficits, mood disorders, and behavioral changes which are progressive over the course of the disease. While a wide range of potential therapeutics are under investigation in both animal models of HD and human clinical trials, currently there is no cure for the illness. In particular the exact cellular and/or molecular mechanisms linking polyQ (CAG) expansion in the Huntingtin protein and disease progression continue to evade us. Therefore in order to rationally develop therapeutic options to treat or slow HD there is a need to understand the underlying biophysical processes, such as structure, aggregation, and binding of the Huntington (Htt) protein. We are using high performance computing (HPC), structural biology modeling, and advanced molecular dynamics (MD) simulation techniques to systematically study the structure and binding (both homotypic and heterotypic) of the Htt exon 1 sequence at high-resolution and design novel inhibitors in silico.
1. Das, P.*, et al. "Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations." PloS one 9.11 (2014): e113041.
2. Das, P.*, Murray, B., Belfort, G. "Alzheimer’s Protective A2T Mutation Changes the Conformational Landscape of the Aβ 1–42 Monomer Differently Than Does the A2V Mutation." Biophysical journal 108.3 (2015): 738-747.
3. Murray, B., et al. "A2T and A2V Aβ Peptides Exhibit Different Aggregation Kinetics, Primary Nucleation, Morphology, Structure and LTP Inhibition."Proteins: Structure, Function, and Bioinformatics (2016).
4. Das, P.*, Chacko, A., Belfort, G. "Alzheimer’s Protective Cross-interaction Between Wild-type and A2T Variants Alters Aβ42 Dimer Structure." ACS Chemical Neuroscience (2016). DOI: 10.1021/acschemneuro.6b00357