Monitoring the folding kinetics of a β-hairpin by time-resolved IR spectroscopy in silico

J Phys Chem B. 2015 Apr 9;119(14):4849-56. doi: 10.1021/acs.jpcb.5b01477. Epub 2015 Mar 31.

Abstract

Protein folding is one of the most fundamental problems in modern biochemistry. Time-resolved infrared (IR) spectroscopy in the amide I region is commonly used to monitor folding kinetics. However, associated atomic detail information on the folding mechanism requires simulations. In atomistic simulations structural order parameters are typically used to follow the folding process along the simulated trajectories. However, a rigorous test of the reliability of the mechanisms found in the simulations requires calculation of the time-dependent experimental observable, i.e., in the present case the IR signal in the amide I region. Here, we combine molecular dynamics simulation with a mixed quantum mechanics/molecular mechanics theoretical methodology, the Perturbed Matrix Method, in order to characterize the folding of a β-hairpin peptide, through modeling the time-dependence of the amide I IR signal. The kinetic and thermodynamic data (folding and unfolding rate constants, and equilibrium folded- and unfolded-state probabilities) obtained from the fit of the calculated signal are in good agreement with the available experimental data [Xu et al. J. Am. Chem. Soc. 2003, 125, 15388-15394]. To the best of our knowledge, this is the first report of the simulation of the time-resolved IR signal of a complex process occurring on a long (microsecond) time scale.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Computer Simulation*
  • Kinetics
  • Molecular Dynamics Simulation*
  • Molecular Sequence Data
  • Peptides / chemistry*
  • Protein Folding*
  • Protein Structure, Secondary
  • Spectrophotometry, Infrared
  • Time Factors

Substances

  • Peptides