The ongoing integration of quantum chemistry, statistical mechanics, and artificial intelligence is paving the route toward more effective and accurate strategies for the investigation of the spectroscopic properties of medium-to-large size chromophores in condensed phases. In this context we are developing a novel workflow aimed at improving the generality, reliability, and ease of use of the available computational tools. In this paper we report our latest developments with specific reference to unsupervised atomistic simulations employing non periodic boundary conditions (NPBC) followed by clustering of the trajectories employing optimized feature spaces. Next accurate variational computations are performed for a representative point of each cluster, whereas intracluster fluctuations are taken into account by a cheap yet reliable perturbative approach. A number of methodological improvements have been introduced including, e.g., more realistic reaction field effects at the outer boundary of the simulation sphere, automatic definition of the feature space by continuous perception of solute-solvent interactions, full account of polarization and charge transfer in the first solvation shell, and inclusion of vibronic contributions. After its validation, this new approach has been applied to the challenging case of solvatochromic effects on the UV-vis spectra of a prototypical nitroxide radical (TEMPO) in different solvents. The reliability, effectiveness, and robustness of the new platform is demonstrated by the remarkable agreement with experiment of the results obtained through an unsupervised approach characterized by a strongly reduced computational cost as compared to that of conventional quantum mechanics and molecular mechanics models without any accuracy reduction.

The parent organometallic complex, methyllithium, is synthesized and characterised in its monomeric form for the first time. This is enabled by a bespoke multidentate neutral amine ligand, namely DETAN.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor whose ligand-induced conformational changes, primarily driven by helix 12 (H12) repositioning, regulate transcriptional activity. However, the precise mechanism remains elusive. In this study, we performed classical molecular dynamics (cMD) simulations of the PPARγ ligand binding domain (LBD) in complex with two agonists (BRL, 3EA), a partial agonist (GW0072), and an antagonist (EKP), generating 3 μs trajectories for each system. To gain deeper insights, we integrated machine learning-assisted clustering with MD simulations, revealing a favorable trend in binding free energy (ΔG _b), suggesting enhanced complex stability. A case study on EKP demonstrated that, despite fitting within the binding site, it failed to induce rapid LBD or H12 rearrangements in the apo agonist-induced conformation. Additionally, we investigated the apo-state conformations of PPARγ-LBD influenced by agonist and antagonist ligands, utilizing cMD and Gaussian accelerated molecular dynamics (GaMD) over a cumulative 6 μs (3 μs cMD + 3 μs GaMD). Key residues known to modulate PPARγ function upon mutation were analyzed, and simulations confirmed the high stability of both apo and ligand-bound conformations. Notably, in the apo state, specific H12 residues interacted with other PPARγ-LBD regions, preventing disorder and abrupt transitions. These findings guided the selection of collective variables (CVs) for well-tempered metadynamics (WT-MetaD) simulations, which-in the apo-agonist state-captured the H12 shift from agonist- to antagonist-like conformations, consistent with resolved X-ray structures. Overall, this computational framework provides novel insights into PPARγ-LBD conformational dynamics and establishes a valuable approach for rationally assessing the effects of modulators on PPARγ activity.