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

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

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†Department of Physical and Chemical Sciences, University of L'Aquila, via Vetoio (Coppito 1), 67010 L'Aquila, Italy.
‡CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110020, India.
¶University of Tennessee/Oak Ridge National Laboratory, Center for Molecular Biophysics, P.O. Box 2008, Oak Ridge, Tennessee 37831-6309, United States.
⊗Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, M407 Walters Life Sciences, 1414 Cumberland Avenue, Knoxville, Tennessee 37996, United States.
§Department of Chemical Sciences and Technologies, University of Rome "Tor Vergata", via della Ricerca Scientifica 1, 00133 Rome, Italy.


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.

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