Unfolding Dynamics of a Photoswitchable Helical Peptide

Abstract

We present an atomistic force field for the azo-moiety of the photo-switchable FK-11-X peptide. We use the parameters to study the unfolding of the peptide through molecular dynamics simulations. The unfolded ensemble contains many different structures, ranging from a partially unfolded peptide to a fully unfolded structure. The averaged computed far-ultraviolet circular dichroism (CD) spectrum of the set of structures, which were simulated using the newly developed force field, agrees well with experiment.The rate of the simulated unfolding process was estimated to have a time constant of 5.80±0.03 ns from the time-evolution of the CD spectrum of the peptide, computed from the backbone conformations sampled over 40 simulated trajectories. Our estimated time constant is faster than, but not inconsistent with, previous experimental estimates from time-resolved infrared and optical rotatory dispersion spectroscopy.

Advances in Application of Azobenzene as a Trigger in Biomedicine: Molecular Design and Spontaneous Assembly

“…Hirst and co‐workers [ 256 ] studied the unfolding process of the FK‐11‐X peptide using computer simulations of molecular dynamics. The results of the unfolding process of FK11‐X based on the atomic force field provided insight into the transient conformations of small peptides during the unfolding process as a supplement to experimental measurements.…”

An Improved Diabatization Scheme for Computing the Electronic Circular Dichroism of Proteins

“…Empirical-based techniques have been developed to predict protein CD spectra from protein atomic coordinates, for example, the SESCA method of Nagy and coworkers 8 which can be compared to the PDB2CD method of Mavridis and Janes, 9 and the recent KCD method of Jacinto-Meńdez et al 10 Calculations of the CD spectra of polypeptides from first-principles 11 afford a direct connection between molecular simulations and experiment, and thereby insights with a spatial and temporal resolution that could not be realized by experiment alone. Examples range from the photoisomerization of azo-peptides 12 through to the binding of proteins to silica. 13 Physics-based techniques have been developed to compute the infrared absorption and the vibrational CD of biomolecules.…”

Understanding the Fast-Triggering Unfolding Dynamics of FK-11 upon Photoexcitation of Azobenzene

“…In addition, Auvray et al conducted 40 × 120 ns MD trajectories to simulate the unfolding process of FK-11-X and observed the transition to completely unfolded conformation in one trajectory. 18 They also computed the time-dependent CD spectrum at 222 nm (typical wavelength for α-helix) by averaging over the 40 trajectories and used single-exponential fitting to obtain a time constant of 5.80 ± 0.03 ns for the unfolding process, 18 which is faster than the previous experimental data. 16 Although the previous studies have made great efforts to investigate the conformational dynamics of the FK peptide and understand its interplay with the isomerization of azobenzene, it is still challenging to statistically simulate the conformational evolution of the FK peptide fast-triggered by the photoexcitation of azobenzene and fully comprehend the underlying molecular mechanisms.…”

“…Further comparison with the simulations without the cross-linker suggested that azobenzene can accelerate the folding/unfolding process of FK-11. In addition, Auvray et al conducted 40 × 120 ns MD trajectories to simulate the unfolding process of FK-11-X and observed the transition to completely unfolded conformation in one trajectory . They also computed the time-dependent CD spectrum at 222 nm (typical wavelength for α-helix) by averaging over the 40 trajectories and used single-exponential fitting to obtain a time constant of 5.80 ± 0.03 ns for the unfolding process, which is faster than the previous experimental data …”