Abstract
The aggregation modes of hexapeptide fragments of Tau, Insulin and Aβ peptide (VQIVYK, MVGGVV and LYQLEN) were found from their microcrystalline structures that had been recently resolved by X-ray analysis. The atomic structures reveal a dry self-complementary interface between the neighboring β-sheet layers, termed “steric zipper”. In this study we perform several all-atom molecular dynamics simulations with explicit water to analyze stability of the crystalline fragments of 2-10 hexapeptides each and their analogs with single glycine replacement mutations to investigate the structural stability, aggregation behavior and thermodynamic of the amyloid oligomers. Upon comparing single and double layer models, our results reveal that additional strands contribute significantly to the structural stability of the peptide oligomers for double layer model, while in the case of single layer model the stability decreases (or remains the same in the case of LYQLEN). This is in agreement with the previous studies performed on different types of amyloid models. We also replaced the side-chains participating in the steric zipper interfaces with glycine. None of the mutants were structurally stable compared to the respective wild type model, except for mutants V2G and V6G in MVGGVV2 case. The exception can be explained by structural features of this particular polymorph. The double layer decamer and dodecamer aggregates of the wild type hexapeptides appear to be stable at 300K, which is confirmed by the conservation of high anti-parallel β-sheet content throughout the whole simulation time. Deletions of the side chains resulted in decline of secondary structure content compared to corresponding wild type indicating that the role of the replaced amino acid in stabilizing the structure. Detailed analysis of the binding energy reveals that stability of these peptide aggregates is determined mainly by the van der Waals and hydrophobic forces that can serve as quantitative measure of shape complementarities between the side chains. This observation implies that interactions among side chains forming the dehydrated steric zipper, rather than among those exposed to water, are the major structural determinant. The electrostatic repulsion destabilizes the studied double layer aggregates in two cases, while stabilizes the other two. Negative total binding free energy indicates that both wild type and mutants complex formation is favorable. However, the mutants complexation is less favorable than the wild type’s. The present study provides the atomic level understanding of the aggregation behavior and the driving force for the amyloid aggregates, and could be useful for rational design of amyloid inhibitors and amyloid-specific biomarkers for diagnostic purposes.
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Acknowledgments
This work was supported in part by the National Science Foundation (CCF/CHE 0832622). This research used resources of the National Energy Research Scientific Computing Center, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. The author appreciates the anonymous reviewers for their insightful comments, which greatly helped improving this paper.
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Berhanu, W.M., Masunov, A.E. Can molecular dynamics simulations assist in design of specific inhibitors and imaging agents of amyloid aggregation? Structure, stability and free energy predictions for amyloid oligomers of VQIVYK, MVGGVV and LYQLEN. J Mol Model 17, 2423–2442 (2011). https://doi.org/10.1007/s00894-010-0912-4
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DOI: https://doi.org/10.1007/s00894-010-0912-4