Tracking Conformational Dynamics of Polypeptides by Nonlinear Electronic Spectroscopy of Aromatic Residues: A First‐Principles Simulation Study

Abstract

The ability of non-linear electronic spectroscopy to track folding/unfolding processes of proteins in solution by monitoring aromatic interactions is investigated by first-principle simulations of two-dimensional (2D) electronic spectra of a model peptide. A dominant reaction pathway approach is employed to determine the unfolding pathway of a tetrapeptide, connecting the initial folded configuration with stacked aromatic side chains and the final unfolded state with distant non-interacting aromatic residues. π-stacking and excitonic coupling effects are included via ab-initio simulations based on multiconfigurational methods within a hybrid QM/MM scheme. We show that linear absorption spectroscopy in the ultraviolet (UV) is unable to resolve the unstacking dynamics characterized by the three-step process: T-shaped→twisted offset stacking→unstacking. Conversely, pump-probe spectroscopy can be used to resolve aromatic interactions by probing in the visible (Vis) the excited state absorptions (ESA) that involve charge transfer (CT) states. 2DUV spectroscopy offers the highest sensitivity to the unfolding process, providing the disentanglement of ESA signals belonging to different aromatic chromophores and high correlation between the conformational dynamics and the quartic splitting.

Modeling the high-energy electronic state manifold of adenine: Calibration for nonlinear electronic spectroscopy

“…62 Our calculations show that these two bands are associated with transitions from the GS to the L − 1 (B b ) and L − 2 (B a ) states, which constitute the most intense transitions in the UV spectra of indole, benzene, and phenol as well. 27,42,46,57,72 Roos and co-workers also arrived at similar conclusions about the nature of the most intense transitions. As with the L b/a states, our calculations tend to overestimate the transition energies for bands III-VI by up to 0.30 eV (Table I).…”

“…[19][20][21][22] Nevertheless, parameterized exciton models are commonly applied to study molecular aggregates as they allow for increasing the aggregate size at virtually no cost. In order to obtain more accurate estimates, we have recently introduced a computational protocol based on a sum-overstates approach 23 where ab initio calculations for dimeric and multimeric systems within a quantum mechanics/molecular mechanics (QM/MM) scheme 18,[24][25][26][27] are coupled with nonlinear response theory, 28 so as to give a better account of the inter-monomer and monomer-solvent interaction effects simultaneously. Within this approach, the dimeric or multimeric system is treated at an ab initio level, thus including the interaction between monomers giving rise to mixed doubly excited and CT states, providing unique fingerprints arising from these interactions that allow disentangling the spectral signals to differentiate specific conformations along folding and unfolding protein processes, 18,27 or to those signals arising due to stacking interactions in a DNA/RNA double-stranded chain.…”

Spectral lineshapes in nonlinear electronic spectroscopy

“…The good agreement with the experimental results validates the formulated theoretical model. Beyond the presented example the single trajectory approximation (eqn (15)), in cooperation with multi-dimensional spectroscopy, can find application in resolving the spectral signatures of different ground state conformers, 55,56 as well as in tracking the photochemistry/photophysics on multiple bright states which are simultaneously excited in the FC region (e.g. the L b , L a , and np* states in native DNA and its building blocks 8,57,58 ).…”

DichroCalc: Improvements in Computing Protein Circular Dichroism Spectroscopy in the Near-Ultraviolet

“…Several theoretical studies [26][27][28] have investigated the distinctive signatures that amyloid fibrils show in the near-UV as well as those of other proteins [29]. MD simulation and calculations of two-dimensional near-UV spectroscopy have been used to monitor the unfolding of a tetrapeptide after photo-induced reduction of an internal disulfide bond [30].…”