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Unique example of amyloid aggregates stabilized by main chain H-bond instead of the steric zipper: molecular dynamics study of the amyloidogenic segment of amylin wild-type and mutants

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Abstract

Most proteins do not aggregate while in their native functional states. However, they may be disturbed from their native conformation by certain change in the environment, and form unwanted oligomeric or polymeric aggregates. Recent experimental data demonstrate that soluble oligomers of amyloidogenic proteins are responsible for amyloidosis and its cytotoxicity. Human islet amyloid polypeptide (IAPP or amylin) is a 37-residue hormone found as fibrillar deposits in pancreatic extracts of nearly all type II diabetics. In this study we performed in silico mutation analysis to examine the stability of the double layer five strand aggregates formed by heptapeptide NNFGAIL segment from amyline peptide. This segment is one of the shortest fragments that can form amyloid fibrils similar to those formed by the full length peptide. The mutants obtained by single glycine replacement were also studied to investigate the specificity of the dry self-complementary interface between the neighboring β-sheet layers. The molecular dynamics simulations of the aggregates run for 20 ns at 330 K, the degree of the aggregate disassembly was investigated using several geometry analysis tools: the root mean square deviations of the Cα atoms, root mean square fluctuations per residue, twist angles, interstrand distances, fraction of the secondary structure elements, and number of H-bonds. The analysis shows that most mutations make the aggregates unstable, and their stabilities were dependent to a large extent on the position of replaced residues. Our mutational simulations are in agreement with the pervious experimental observations. We also used free binding energy calculations to determine the role of different components: nonpolar effects, electrostatics and entropy in binding. Nonpolar effects remained consistently more favorable in wild type and mutants reinforcing the importance of hydrophobic effects in protein-protein binding. While entropy systematically opposed binding in all cases, there was no clear trend in the entropy difference between wildtype and glycine mutants. Free energy decomposition shows residues situated at the interface were found to make favorable contributions to the peptide-peptide association. The study of the wild type and mutants in an explicit solvent could provide valuable insight into the future computer guided design efforts for the amyloid aggregation inhibitor.

The structure of NNFGAIL aggregate lacks side-chain steric-zipper interlocking. Instead, the β-sheet stacking is stabilized by the main chains packing.

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Acknowledgments

This work was supported in part by the National Science Foundation (CHE0832622), and used the resources of the National Energy Research Scientific Computing Center (NERSC), which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. The authors are thankful to Dr. Michael Sawaya for providing the initial aggregate models, and for his helpful discussions. WMB also thanks Dr. Zhengji Zhao of NERSC for her help with the software installation.

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  1. NanoScience Technology Center and Department of Chemistry, University of Central Florida, Orlando, FL, 32826, USA

    Workalemahu Mikre Berhanu

  2. NanoScience Technology Center, Department of Chemistry, and Department of Physics, University of Central Florida, Orlando, FL, 32826, USA

    Artëm E. Masunov

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  1. Workalemahu Mikre Berhanu
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Correspondence to Artëm E. Masunov.

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Berhanu, W.M., Masunov, A.E. Unique example of amyloid aggregates stabilized by main chain H-bond instead of the steric zipper: molecular dynamics study of the amyloidogenic segment of amylin wild-type and mutants. J Mol Model 18, 891–903 (2012). https://doi.org/10.1007/s00894-011-1030-7

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