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We introduce the basic concepts of two-dimensional electronic spectroscopy (2DES) and a general theoretical framework adopted to calculate, from first principles, the nonlinear response of multi-chromophoric systems in realistic environments. Specifically, we focus on UV-active chromophores representing the building blocks of biological systems, from proteins to nucleic acids, describing our progress in developing computational tools and protocols for accurate simulation of their 2DUV spectra. The roadmap for accurate 2DUV spectroscopy simulations is illustrated starting with benchmarking of the excited-state manifold of the chromophoric units in a vacuum, which can be used for building exciton Hamiltonians for large-scale applications or as a reference for first-principles simulations with reduced computational cost, enabling treatment of minimal (still realistic) multi-chromophoric model systems. By adopting a static approximation that neglects dynamic processes such as spectral diffusion and population transfer, we show how 2DUV is able to characterize the ground-state conformational space of dinucleosides and small peptides comprising dimeric chromophoric units (in their native environment) by tracking inter-chromophoric electronic couplings. Recovering the excited-state coherent vibrational dynamics and population transfers, we observe a remarkable agreement between the predicted 2DUV spectra of the pyrene molecule and the experimental results. These results further led to theoretical studies of the excited-state dynamics in a solvated dinucleoside system, showing that spectroscopic fingerprints of long-lived excited-state minima along the complex photoinduced decay pathways of DNA/RNA model systems can be simulated at a reasonable computational cost. Our results exemplify the impact of accurate simulation of 2DES spectra in revealing complex physicochemical properties of fundamental biological systems and should trigger further theoretical developments as well as new experiments.

Since the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), several variants have caused a persistent pandemic. Consequently, it is crucial to develop new potential anti-SARS-CoV-2 drugs with specificity. To minimize potential failures and preserve valuable clinical resources for the development of other useful drugs, researchers must enhance their understanding of the interactions between drugs and SARS-CoV-2. While numerous crystal structures of the SARS-CoV-2 main protease (SCM) and its inhibitors have been reported, they provide only static snapshots and fail to capture the dynamic nature of SCM/inhibitor interactions. Herein, we conducted molecular dynamics simulations for five SCM complexes: ritonavir (SCM/RTV), lopinavir (SCM/LPV), the identified inhibitor N3 (SCM/N3), the approved inhibitor ensitrelvir (SCM/ESV), and the approved drug nirmatrelvir (SCM/NMV). Additionally, we explored the potential for covalent bond formation in the N3 and NMV inhibitors through QM/MM calculations using Umbrella sampling. The results show that the binding site is highly flexible to fit those five different inhibitors and each compound has its unique binding mode at the same binding site. Moreover, the binding affinities of positive and negative inhibitors to SCM exhibit significant differences. By gaining insights into the dynamics, we can potentially elucidate why lopinavir/ritonavir, initially considered promising, failed to effectively treat COVID-19. Furthermore, understanding the mechanistic aspects of N3 and NMV inhibition on SCM not only contributes to rational drug discovery against COVID-19 but also aids future studies on the catalytic mechanisms of main proteases in other novel coronaviruses.Communicated by Ramaswamy H. Sarma.

Despite the fact that DNA molecule is studied up and down, we know very little about the role of DNA triplets in coding amino acids and stop-codons. The paper aims to fill this gap through attracting spintronic ideas and carrying out QM/MM computations on a full-turn DNA fragment. The computations reveal two hidden symmetries: the spin splitting (the Rashba effect), confined within each triplet, and the quantum “phase” link between the triplet nature (in total, 64 triplets) and the corresponding amino acid and three stop-codons. The hidden symmetries become evident upon binding the magnesium cofactor to DNA triplets in 5’−3’ and 3’−5’ directions. [ABSTRACT FROM AUTHOR]

The temperature dependence of H- Uiso in N-acetyl-L-4-hydroxyproline monohydrate is investigated. Imposing a constant temperature-independent multiplier of 1.2 or 1.5 for the riding hydrogen model is found to be inaccurate, and severely underestimates H- Uiso below 100 K. Neutron diffraction data at temperatures of 9, 150, 200 and 250 K provide benchmark results for this study. X-ray diffraction data to high resolution, collected at temperatures of 9, 30, 50, 75, 100, 150, 200 and 250 K (synchrotron and home source), reproduce neutron results only when evaluated by aspherical-atom refinement models, since these take into account bonding and lone-pair electron density; both invariom and Hirshfeld-atom refinement models enable a more precise determination of the magnitude of H-atom displacements than independent-atom model refinements. Experimental efforts are complemented by computing displacement parameters following the TLS+ONIOM approach. A satisfactory agreement between all approaches is found. [ABSTRACT FROM AUTHOR]

In the field of spin trapping chemistry, we proposed a promising new theoretical QM/MM//MD combined protocol to assist the development of new nitrone-based spin traps (Houriez et al. in J Phys Chem B 114:11793-11803, ). In the present study, we test its accuracy and its transferability by investigating the spectromagnetic properties in water of DMPO-OH, the nitroxide spin adduct of the 5,5-dimethyl-1-pyrroline- N-oxide nitrone (DMPO) with the OH radical. Thanks to our theoretical method, we obtain quantitative estimates of the DMPO-OH hyperfine coupling constants (hcc's) in very good agreement with experiment. Moreover, our study reveals that the DMPO-OH hcc values are related to the main features of an equilibrium between two major conformations of the nitroxide five-membered ring. Together with our earlier results, the present study clearly establishes the reliability of our theoretical protocol to investigate in condensed phase the behavior of flexible and large nitroxides. Particularly, note that with our method, it is possible to point out clearly fundamental differences in spectromagnetic properties even for two molecules very similar in geometrical structure. [ABSTRACT FROM AUTHOR]

The "open" (A open) and "closed" (A closed) A-clusters of the acteyl-CoA synthase (ACS) enzyme from Moorella thermoacetica have been studied using a combined quantum mechanical (QM)/molecular mechanical (MM) approach. Geometry optimizations of the oxidized, one- and two-electron reduced A open state have been carried out for the fully solvated ACS enzyme, and the CO ligand has been modeled in the reduced models. Using a combination of both α open and α closed protein scaffolds and the positions of metal atoms in these structures, we have been able to piece together critical parts of the catalytic cycle of ACS. We have replaced the unidentified exogenous ligand in the crystal structure with CO using both a square planar and tetrahedral proximal Ni atom. A one-electron reduced A-cluster that is characterized by a proximal Ni atom in a tetrahedral coordination pattern observed in both the A open (lower occupancy proximal Ni) and A closed (proximal Zn atom) geometries with three cysteine thiolates and a modeled CO ligand demonstrates excellent agreement with the crystal structure atomic positions, particularly with the displacement of the side chain ring of Phe512 which appears to serve as a structural gate for ligand binding. The QM/MM optimized geometry of the A-cluster of ACS with an uncoordinated, oxidized proximal nickel atom in a square planar geometry demonstrates poor agreement with the atomic coordinates taken from the crystal structure. Based on these calculations, we conclude that the square planar proximal nickel coordination that has been captured in the A open structure does not correspond to the ligand-free, oxidized [Fe 4 S 4 ]2+ − Ni p 2+ − Ni d 2+ state. Overall, these computations shed further light on the mechanistic details of protein conformational changes and electronic transitions involved in the ACS catalytic cycle. • QM/MM computations reveal atomic details of A open and A closed catalytic centers in acetyl-CoA synthase (ACS) • Geometry of one-electron reduced A-cluster with CO ligand and tetrahedral proximal Ni atom agrees with the crystal structure • Rotation of the side chain ring of Phe512 appears to serve as a structural gate for ligand binding • A open with square planar proximal nickel does not correspond to the ligand-free, oxidized [Fe 4 S 4 ]2+--Ni p 2+--Ni d 2+ state [ABSTRACT FROM AUTHOR]

The temperature dependence of H-U(iso) in N-acetyl-L-4-hydroxyproline monohydrate is investigated. Imposing a constant temperature-independent multiplier of 1.2 or 1.5 for the riding hydrogen model is found to be inaccurate, and severely underestimates H-U(iso) below 100 K. Neutron diffraction data at temperatures of 9, 150, 200 and 250 K provide benchmark results for this study. X-ray diffraction data to high resolution, collected at temperatures of 9, 30, 50, 75, 100, 150, 200 and 250 K (synchrotron and home source), reproduce neutron results only when evaluated by aspherical-atom refinement models, since these take into account bonding and lone-pair electron density; both invariom and Hirshfeld-atom refinement models enable a more precise determination of the magnitude of H-atom displacements than independent-atom model refinements. Experimental efforts are complemented by computing displacement parameters following the TLS+ONIOM approach. A satisfactory agreement between all approaches is found.