title: Virtual atom representation of hydrogen bonds in minimal off-lattice models of alpha helices: effect on stability, cooperativity and kinetics.
abstract: BACKGROUND
  The most conspicuous feature of a right-handed alpha helix is the presence of hydrogen bonds between the backbone carbonyl oxygen and NH groups along the chain. A simple off-lattice model that includes hydrogen bond interactions using virtual atoms is used to examine the stability, cooperativity and kinetics of the helix-coil transition.
  
  
  RESULTS
  We have studied the thermodynamics (using multiple histogram method) and kinetics (by Brownian dynamics simulations) of 16-mer minimal off-lattice models of four-turn alpha-helix sequences. The carbonyl and NH groups are represented as virtual moieties located between two alpha-carbon atoms along the polypeptide chain. The characteristics of the native conformations of the model helices, such as the helical pitch and angular correlations, coincide with those found in real proteins. The transition from coil to helix is quite broad, which is typical of these finite-sized systems. The cooperativity, as measured by a dimensionless parameter, omegac, that takes into account the width and the slope of the transition curves, is enhanced when hydrogen bonds are taken into account. The value of omegac for our model is consistent with that inferred from experiment for an alanine-based helix-forming peptide. The folding time tauF ranges from 6 to 1000 ns in the temperature range 0.7-1.9 T(F), where T(F) is the helix-coil transition temperature. These values are in excellent agreement with the results from recent fast folding experiments. The temperature dependence of tauF exhibits a nearly Arrhenius behavior. Thermally induced unfolding occurs on a time scale that is less than 40-170 ps depending on the final temperature. Our calculations also predict that, although tauF can be altered by changes in the sequence, the dynamic range over which such changes take place is not as large as that predicted for beta-turn formation.
  
  
  CONCLUSIONS
  Hydrogen bonds not only affect the stability of alpha-helix formation but also have profound influence on the kinetics. The excellent agreement between our calculations and experiments suggests that these models can be used to investigate the effects of sequence, temperature and viscosity on the helix-coil transition.
authors.affiliation: Institute for Physical Science and Technology and Department of Chemistry and Biochemistry, University of Maryland, College Park 20742, USA. klimov@glue.umd.edu
authors.forename: D K
authors.initials: DK
authors.lastname: Klimov
authors.forename: M R
authors.initials: MR
authors.lastname: Betancourt
authors.forename: D
authors.initials: D
authors.lastname: Thirumalai
mesh_terms: D000818:Animals; D006801:Humans; D006859:Hydrogen; D007700:Kinetics; D008958:Models, Molecular; D011489:Protein Denaturation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D011506:Proteins; D006859:Hydrogen