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Free energy simulations of amylin I26P mutation in a lipid bilayer

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Abstract

The amylin peptide in a dioleoylphosphatidylcholine (DOPC) bilayer is studied using united atom molecular dynamics (MD) simulations. Dynamics and transport properties of the peptide and the phospholipid bilayer are investigated. The lateral diffusion of DOPC is in the order of 10−8 cm2 s−1, which is in agreement with the experimental results. The order parameter and density profile for phospholipid molecules in the bilayer are calculated. The secondary structure of amylin peptide shows that the amino acids in two terminals are structureless and two α-helical segments in the peptide are connected through an unstructured link. This structure is similar to the experimental structure in the membrane-mimicking media. Free energy calculations of the Ile26 → Pro mutation in the amylin peptide are performed in the bilayer and in aqueous solution using molecular dynamics simulations and a thermodynamic cycle. It is shown that in the mutated peptide in aqueous solution, the α-helix structure changes to a 5-helix, whereas this configuration is preserved in the bilayer environment. It is interesting that the accessible surface area increases for hydrophobic residues in the bilayer and for hydrophilic residues in aqueous solution as the coupling parameter changes from 0 to 1. These results are significant to understanding the aggregation mechanism of human amylin monomers in membranes to the dimers, trimers, oligomers, and fibrils associated with the type 2 diabetes at the atomic level.

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Acknowledgments

This work was supported by the Theoretical and Computational Physical Chemistry Laboratory at K.N. Toosi University of Technology.

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Authors and Affiliations

  1. Department of Chemistry, K.N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran

    Seifollah Jalili

  2. Department of Nano-Science, Computational Physical Sciences Research Laboratory, Institute for Studies in Theoretical Physics and Mathematics (IPM), P.O. Box: 19395-5531, Tehran, Iran

    Seifollah Jalili & Mojdeh Akhavan

  3. Department of Chemistry, Islamic Azad University, Omidiyeh Branch, Omidiyeh, Khuzestan, Iran

    Afsaneh Maleki

  4. Department of Chemistry, Isfahan University of Technology, Isfahan, Iran

    Bijan Najafi

  5. Department of Chemistry, Chemical Physics Theory Group, University of Toronto, 80 Saint George Street, Toronto, ON, M5S 3H6, Canada

    Jeremy Schofield

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  1. Seifollah Jalili
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  2. Afsaneh Maleki
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Correspondence to Afsaneh Maleki.

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249_2014_999_MOESM1_ESM.doc

The calculated MSDs for the DOPC bilayer in the range of 40 ns are presented in figure S1. Final conformations of amylin for simulations at six different λ values in the solvent and bilayer environment are given in figure S2. dG/dλ versus time and their cumulative average for lambda = 0.7, 0.75, 0.9, and 0.95 for peptide in aqueous solution are shown in figure S3. The number of hydrogen bonds formed between native hIAPP and the lipid bilayer in λ = 0 and between mutated hIAPP and the lipid bilayer in λ = 1 are presented in figure S4. (DOC 2861 kb)

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Jalili, S., Maleki, A., Akhavan, M. et al. Free energy simulations of amylin I26P mutation in a lipid bilayer. Eur Biophys J 44, 37–47 (2015). https://doi.org/10.1007/s00249-014-0999-0

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  • DOI: https://doi.org/10.1007/s00249-014-0999-0

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