We use MD simulations to characterize the solution features of peptide species that play a central role in the molecular pathology of Alzheimer's disease (AD), the amyloid-β peptides (Aβ). Aggregation of Aβ leads to various β-sheet rich conformers that are found in the brains of AD patients and correlate with the onset of AD. Moreover, Aβ oligomerization leads to the formation of neurotoxic oligomeric species that have been hypothesized to inhibit synapse transmission. We have optimized and applied enhanced-sampling MD simulations to characterize the key structural features of the monomeric species (Sgourakis et al., Journal of Molecular biology, 2007). We performed simulations for both isoforms of Aβ, Aβ40 and Aβ42, motivated by the experimental evidence that Aβ42 shows enhanced aggregation and toxicity. Since these results are limited by the extent of conformational sampling and depend on the details of the forcefield used, we applied a variety of forcefields and validated our results through direct comparison with experimental data from Nuclear Magnetic Resonance (NMR - collaboration with Chunyu Wang, Yilin Yan and Scott McCallum, at RPI). NMR is particularly suited for the study of the dynamics of biomolecules that occur over a range of timescales and atomic degrees of freedom. MD is a unique methodology for developing structural models to interpret NMR data at the relevant timescales. Our results correlate well with experimental measurements and provide a description of the conformational properties of these important peptides in full atomic resolution that contradicts their perception as structurally uniform “random coils”. We postulate how structural differences between the two peptides at the monomeric level may result in differences in their aggregation profiles. Therefore, our findings provide a rationale for the design of aggregation inhibitors that would preferentially stabilize non-amyloidogenic conformations of the monomeric species with potential for drug development.
The ensemble of Abeta(1-42) in water can be classified in four major clusters with unique structural properties which challenges the view of Abeta as a featureless, 'random coil' peptide. Contact maps calculated for each cluster indicate interacting regions within the peptide sequence, such as the central hydrophobic cluster region 16-22, which is implicated in the aggregation process and has been used as a template for the design of aggregation inhibitors. These MD-derived results are validated through direct comparison with experimental J-coupling values from NMR experiments and provide a structural insight into the aggreagtion-competent conformations.
- '"Characterization of Aβ Monomers through the Convergence of Ensemble Properties among Simulations with Multiple Force Fields ' David J. Rosenman, Chunyu Wang, and Angel E. García, J. Phys. Chem. B, 2016, 120, 259−277. Publication Date (Web): November 12, 2015 (Feature Article) DOI: 10.1021/acs.jpcb.5b09379 [ http://dx.doi.org/10.1021/acs.jpcb.5b09379 link].
- '"Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies' Jessica Nasica-Labouze, Phuong H Nguyen, Fabio Sterpone, Olivia Berthoumieu, Nicolae-Viorel Buchete, Sébastien Coté, Alfonso De Simone, Andrew J Doig, Peter Faller, Angel Garcia, Alessandro Laio, Mai Suan Li, Simone Melchionna, Normand Mousseau, Yuguang Mu, Anant Paravastu, Samuela Pasquali, David J Rosenman, Birgit Strodel, Bogdan Tarus, John H Viles, Tong Zhang, Chunyu Wang, Philippe Derreumaux. Chem. Rev., 2015, 115 (9), pp 3518–3563. DOI: 10.1021/cr500638n [ http://dx.doi.org/10.1021/cr500638n link]
- '"Aβ monomers transiently sample oligomer and fibril-like configurations: ensemble characterization using a combined MD/NMR approach' D. Rosenman, C. Connors, W. Chen, C. Wang, A.E. García, J. Mol. Biol., 425: 3338-3359 (2013) [ http://dx.doi.org/10.1016/j.jmb.2013.06.021 link].
- Atomic-Level Characterization of the Ensemble of theAb(1–42) Monomer in Water Using Unbiased Molecular Dynamics Simulations and Spectral Algorithms, N.G. Sgourakis, M. Merced-Serrano, C. Boutsidis, P. Drineas, Z. Du, C. Wang and A. E. Garcia“, J Mol. Biol. 405: 570-583 (2011)
- Discriminating early stage Aβ42 monomer structures using chirality-induced 2DIR spectroscopy in a simulation study,"Wei Zhuang, Nikolaos G. Sgourakis, Zhenyu Li, Angel E. Garcia, and Shaul Mukamel. Proc. Natl. Acad. Sci. (USA) 107:15687–15692 (2010).
- The Alzheimer’s peptides Aβ40 and Aβ42 adopt distinct conformations in water: A combined MD/NMR study., N. G. Sgourakis, Y. Yan, S.A. McCAllum, C. Wang, and A.E. Garcia, J. Mol. Biol., 368: 1448-1457 (2007).
- Global versus local features of an unfolded peptide system – Aβ42 modeled by Dynamics simulations and NMR experiments, N. G. Sgourakis, and A.E. Garcia, In book "From Denatured States to Intrinsically Disordered". Vladimir Uversky and T. Creamer, Editors. (2008)
- Atomic-level description of amyloid beta-dimer formation link, Gnanakaran, S; Nussinov, R; Garcia, AE, J Amer. Chem Soc. (Communications) 128: 2158-2159 (2006)