Analysis of Infrared Spectra of β-Hairpin Peptides As Derived from Molecular Dynamics Simulations

Abstract

Infrared temperature-dependent spectroscopy is a well-known tool to characterize folding/unfolding transitions in peptides and proteins, assuming that the higher the temperature, the higher the unfolded population. The infrared spectra at different temperatures of two β-hairpin peptides (gramicidin S analogues GS6 and GS10) are here reconstructed by means of molecular dynamics (MD) simulations and a theoretical-computational method based on the perturbed matrix method. The calculated temperature-dependent spectra result in good agreement with the experimental available spectra. The same methodology has been then used to reconstruct the spectra corresponding to the pure unfolded and folded states, as defined from the MD simulations, in order to better understand the temperature-dependent spectra and to help the interpretation of the experimental spectra. For example, our results show that in the case of the GS6 peptide the analysis of the temperature-dependent spectra cannot be used to investigate the folding/unfolding kinetics within the usual assumption that the higher the temperature, the higher the probability of the unfolded state.

A quantitative connection of experimental and simulated folding landscapes by vibrational spectroscopy

“…This enables statistically relevant sampling of the quantum-center and environment configurations, which is required for accurate IR spectra calculations of proteins. This method has been calibrated recently with static IR spectra of amyloids,21 unfolded protein states,22,23 and equilibrium protein folding,24,25 as well as by calculating reduction potentials26,27 and electron transfer processes28,29 in proteins.…”

Essential dynamics: foundation and applications

“…Despite the enormous number of applications described in literature and its almost a century of existence, PCA is presently not only a widely used tool in most of the fields of atomic–molecular research, but it is still undergoing new developments. Of particular interest for chemical–physical studies are the new applications of PCA on hydrogen‐bonding fluctuations to describe folding–unfolding transitions in peptides and, in principle, secondary structure elements of proteins60 or on electronic state fluctuations to characterize quantum state transitions as provided by perturbation effects 61…”

Monitoring the Folding Kinetics of a β-Hairpin by Time-Resolved IR Spectroscopy in Silico

“…25,30,32 Moreover, the amide I signal originating from any residue of a peptide/protein chain may be isolated allowing the comparison with experimental isotopelabeled spectra. 29 Nevertheless, the PMM/MD methodology may not always reproduce the spectral fine structure.…”

“…The present methodology, based on a fully quantum mechanical treatment of the chromophore vibrations and on extended phase space sampling to rigorously treat the chromophore-environment interaction, was shown, in the present and previous works, to be reliable in reproducing the main spectroscopic features of the amide I band in complex systems, such as amyloids, 29 extended β-sheets 31 and unfolded states of different peptides. 25,30,32 Moreover, the amide I signal originating from any residue of a peptide/protein chain may be isolated allowing the comparison with experimental isotopelabeled spectra. 29 Nevertheless, the PMM/MD methodology may not always reproduce the spectral fine structure.…”

“…In PMM, as in other QM/MM procedures, a portion of the system (the quantum center) is treated at an electronic level, while the rest of the system is described at a classical atomistic level, exerting an electrostatic perturbation on the quantum-center electronic states. As the method makes use of classical MD to provide phase space sampling, statistically relevant sampling of the quantum-center/environment configurations can be achieved, which is required for an accurate calculation of the spectra of complex systems such as amyloids or peptide/protein unfolded states. ,− However, since the PMM methodology does not make use of empirical/adjustable parameters, it can sometimes be less accurate than other methodologies − in reproducing some of the details of the spectroscopic signals.…”