Modeling of folding and unfolding mechanisms in alanine-based alpha-helical polypeptides

J Phys Chem B. 2006 Oct 19;110(41):20555-61. doi: 10.1021/jp061781e.

Abstract

alpha-Helix formation is known to be opposed by the entropy loss due to the folding and favored by the energy of molecular interactions. However, the underlying mechanism of these factors is still being discussed. Here we have used the experimental and calculation data for short alanine-based peptides embedded in water to model the mechanism of helix folding and unfolding and to calculate microscopically the free energy factors of alanine in the frame of helix coil conformational integrals. Classical helix-coil transition theories take into account the interactions in a peptide chain only if the i, i + 3 peptide bond participates in hydrogen bonding. But quantum mechanical calculations showed that interactions of the i, i + 2 peptide bond play an important role in helix folding too. We also included the short-range repulsive interactions due to molecular steric clashes and the end effects due to polar/hydrogen-bonding interactions at the N and C termini. The helix and coil regions of peptide conformational space were defined using an experimental steric criterion for hydrogen bonding. Arginine helix propensity was discussed and estimated. Monte Carlo numerical simulations of thermodynamics and kinetics for the 21 amino acid alpha-helical polypeptide Ac-A5(AAARA)3A-NMe were carried out and found to be in an agreement with the experimental results.

MeSH terms

  • Alanine / chemistry*
  • Arginine / chemistry
  • Chemistry, Physical / methods*
  • Hydrogen Bonding
  • Kinetics
  • Molecular Conformation
  • Monte Carlo Method
  • Peptides / chemistry*
  • Protein Binding
  • Protein Denaturation
  • Protein Folding
  • Protein Structure, Secondary
  • Quantum Theory
  • Static Electricity

Substances

  • Peptides
  • Arginine
  • Alanine