The balance between side-chain and backbone-driven association in folding of the α-helical influenza A transmembrane peptide

Ioannis Stylianakis, Ariella Shalev, Steve Scheiner, Michael P. Sigalas, Isaiah T. Arkin, Nikolas Glykos*, Antonios Kolocouris*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The correct balance between attractive, repulsive and peptide hydrogen bonding interactions must be attained for proteins to fold correctly. To investigate these important contributors, we sought a comparison of the folding between two 25-residues peptides, the influenza A M2 protein transmembrane domain (M2TM) and the 25-Ala (Ala25). M2TM forms a stable α-helix as is shown by circular dichroism (CD) experiments. Molecular dynamics (MD) simulations with adaptive tempering show that M2TM monomer is more dynamic in nature and quickly interconverts between an ensemble of various α-helical structures, and less frequently turns and coils, compared to one α-helix for Ala25. DFT calculations suggest that folding from the extended structure to the α-helical structure is favored for M2TM compared with Ala25. This is due to CH⋯O attractive interactions which favor folding to the M2TM α-helix, and cannot be described accurately with a force field. Using natural bond orbital (NBO) analysis and quantum theory atoms in molecules (QTAIM) calculations, 26 CH⋯O interactions and 22 NH⋯O hydrogen bonds are calculated for M2TM. The calculations show that CH⋯O hydrogen bonds, although individually weaker, have a cumulative effect that cannot be ignored and may contribute as much as half of the total hydrogen bonding energy, when compared to NH⋯O, to the stabilization of the α-helix in M2TM. Further, a strengthening of NH⋯O hydrogen bonding interactions is calculated for M2TM compared to Ala25. Additionally, these weak CH⋯O interactions can dissociate and associate easily leading to the ensemble of folded structures for M2TM observed in folding MD simulations.

Original languageAmerican English
Pages (from-to)2177-2188
Number of pages12
JournalJournal of Computational Chemistry
Issue number25
StatePublished - 30 Sep 2020

Bibliographical note

Publisher Copyright:
© 2020 Wiley Periodicals LLC


  • B3LYP
  • CH⋯O hydrogen bonding
  • D95(d,p)
  • NBO
  • adaptive tempering
  • circular dichroism
  • folding
  • influenza A M2TM
  • molecular dynamics
  • α-helix


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