Solvatochromic charge model of isonitrile probes for investigating hydrogen-bond dynamics with 2DIR spectroscopy

Isonitrile-derivatized amino acids are emerging as highly effective infrared (IR) probes for investigating the structures and dynamics of hydrogen (H)-bonds. These probes enable the quantification of chemical exchange processes in solute-solvent complexes via two-dimensional IR spectroscopy and hold significant promise for site-specific dynamic studies within proteins. Despite their potential, theoretical models that elucidate the solvatochromism of isonitriles remain underdeveloped. Here, we present the development and validation of a solvatochromic charge model for isonitrile (N≡C) probes. Using density functional theory calculations, we parameterized solvatochromic charges for isonitrile and integrated them into classical molecular dynamics (MD) simulations of β-isocyanoalanine in various solvents, including water and fluorinated alcohols. The model incorporates solvent-induced frequency shifts and accurately reproduces complex experimental line shapes, including asymmetric features from non-Gaussian dynamics. The model successfully reproduced the bimodal distribution of frequency shifts corresponding to free and H-bonded species in alcohols, as well as cross-peaks due to chemical exchange. Achieving reproducibility required long MD trajectories, which were computationally demanding. To manage this, we implemented graphics processing unit acceleration, drastically reducing the computational time and enabling the efficient processing of extensive MD data. While some discrepancies in population ratios suggest the need for refined solvent force field parameters and modeling transition dipole moment variations, the developed solvatochromic model is a reliable tool for studying the solvation dynamics. The model enables more detailed investigations of ultrafast dynamics in solute-solvent complexes and represents important steps toward modeling site-specific dynamics of biomolecules with isonitrile probes.