Predicting Solvatochromism of Chromophores in Proteins through QM/MM and Machine Learning.

Solvatochromism occurs in both homogeneous solvents and more complex biological environments, such as proteins. While in both cases the solvatochromic effects report on the surroundings of the chromophore, their interpretation in proteins becomes more complicated not only because of structural effects induced by the protein pocket but also because the protein environment is highly anisotropic. This is particularly evident for highly conjugated and flexible molecules such as carotenoids, whose excitation energy is strongly dependent on both the geometry and the electrostatics of the environment. Here, we introduce a machine learning (ML) strategy trained on quantum mechanics/molecular mechanics calculations of geometrical and electrochromic contributions to carotenoids' excitation energies. We employ this strategy to compare solvatochromism in protein and solvent environments. Despite the important specifities of the protein, ML models trained on solvents can faithfully predict excitation energies in the protein environment, demonstrating the robustness of the chosen descriptors.

Deciphering Photoreceptors Through Atomistic Modeling from Light Absorption to Conformational Response.

In this review, we discuss the successes and challenges of the atomistic modeling of photoreceptors. Throughout our presentation, we integrate explanations of the primary methodological approaches, ranging from quantum mechanical descriptions to classical enhanced sampling methods, all while providing illustrative examples of their practical application to specific systems. To enhance the effectiveness of our analysis, our primary focus has been directed towards the examination of applications across three distinct photoreceptors. These include an example of Blue Light-Using Flavin (BLUF) domains, a bacteriophytochrome, and the orange carotenoid protein (OCP) employed by cyanobacteria for photoprotection. Particular emphasis will be placed on the pivotal role played by the protein matrix in fine-tuning the initial photochemical event within the embedded chromophore. Furthermore, we will investigate how this localized perturbation initiates a cascade of events propagating from the binding pocket throughout the entire protein structure, thanks to the intricate network of interactions between the chromophore and the protein.

Fast Method for Excited-State Dynamics in Complex Systems and Its Application to the Photoactivation of a Blue Light Using Flavin Photoreceptor.

The excited-state dynamics of molecules embedded in complex (bio)matrices is still a challenging goal for quantum chemical models. Hybrid QM/MM models have proven to be an effective strategy, but an optimal combination of accuracy and computational cost still has to be found. Here, we present a method which combines the accuracy of a polarizable embedding QM/MM approach with the computational efficiency of an excited-state self-consistent field method. The newly implemented method is applied to the photoactivation of the blue-light-using flavin (BLUF) domain of the AppA protein. We show that the proton-coupled electron transfer (PCET) process suggested for other BLUF proteins is still valid also for AppA.

A Quasi Time-Reversible Scheme Based on Density Matrix Extrapolation on the Grassmann Manifold for Born-Oppenheimer Molecular Dynamics.

This Letter introduces the so-called Quasi Time-Reversible scheme based on Grassmann extrapolation (QTR G-Ext) of density matrices for an accurate calculation of initial guesses in Born-Oppenheimer Molecular Dynamics (BOMD) simulations. The method shows excellent results on four large molecular systems that are representative of real-life production applications, ranging from 21 to 94 atoms simulated with Kohn-Sham (KS) density functional theory surrounded with a classical environment with 6k to 16k atoms. Namely, it clearly reduces the number of self-consistent field iterations while at the same time achieving energy-conserving simulations, resulting in a considerable speed-up of BOMD simulations even when tight convergence of the KS equations is required.