All-Atom Quantum Mechanical Calculation of the Second-Harmonic Generation of Fluorescent Proteins

Abstract

Fluorescent proteins (FPs) are biotags of choice for second-harmonic imaging microscopy (SHIM). Because of their large size, computing their second-harmonic generation (SHG) response represents a great challenge for quantum chemistry. In this contribution, we propose a new all-atom quantum mechanics methodology to compute SHG of large systems. This is now possible because of two recent implementations: the tight-binding GFN2-xTB method to optimize geometries and a related version of the simplified time-dependent density functional theory (sTD-DFT-xTB) to evaluate quadratic response functions. In addition, a new dual-threshold configuration selection scheme is introduced to reduce the computational costs while retaining overall similar accuracy. This methodology was tested to evaluate the SHG of the proteins iLOV and bacteriorhodopsin (bR). In the case of bR, quantitative agreement with respect to experiment was reached for the out-of-resonance low-energy part of the βHRS frequency dispersion. This work paves the way toward an accurate prediction of the SHG of large structuresa requirement for the design of new and improved SHIM biotags.

Ultrafast Evaluation of Two-Photon Absorption with Simplified Time-Dependent Density Functional Theory

“…The negatively charged FMN chromophore was extracted from the iLOV X-ray structure that was previously used to model its second-harmonic generation. 64 The CREST 89 code was used to sample the conformational space with the GFN2-xTB method 90 considering water as a solvent with the GBSA model. 91 The 37 lowest-energy conformers were selected and optimized at the ωB97X-D/6-31G(d)/IEFPCM level of theory with water as a solvent.…”

“…These calculations for FMN were done with the Gaussian 16 A03 package 92 and the xtb 6.2.2 program. 93,94 The optimized structure of iLOV was taken from the study of Beaujean et al 64 where the full protein including explicit surrounding water molecules was optimized at the ONIOM ωB97X-D3/6-31G(d):GFN2-xTB/GBSA-(water) level.…”

“…Finally, to showcase the performance of the method and in particular of its sTD-DFT-xTB tight-binding version, the 2PA spectrum of the entire protein iLOV was computed and compared to that from the experiment. It was the opportunity to extend the all-atom quantum chemistry methodology we developed to evaluate the first hyperpolarizability 64 of FPs to 2PA. The striking agreement with the experimental results shows undoubtedly the relevance of such an approach.…”

Evaluating fast methods for static polarizabilities on extended conjugated oligomers

“…51 Although designed for orbital energies and electronic spectroscopy, this method has been used successfully for regarding electron density and polarizability calculations in specific cases. [52][53][54][55] Our attempt to use sTDA-xTB yielded worse results, with a linear fit MAE of 15.85 Å (Fig. S4, ESI †).…”

First-order hyperpolarizabilities of propellanes: elucidating structure–property relationships

“…In fact, computer simulations provide an invaluable tool in the analysis of second-order nonlinear optical properties of molecules and their assemblies. [21][22][23][24][25][26][27][28][29] 2 Theory and computational methods…”