π‐Bridge Substitution in DASAs: The Subtle Equilibrium between Photochemical Improvements and Thermal Control

Donor-acceptor Stenhouse adducts (DASAs) are playing an outstanding role as innovative and versatile photoswitches. Until now, all the efforts have been spent on modifying the donor and acceptor moieties to modulate the absorption energy and improve the cyclization and reversion kinetics. However, there is a strong dependence on specific structural modifications and a lack of predictive behavior, mostly owing to the complex photoswitching mechanism. Here, by means of a combined experimental and theoretical study, the effect of chemical modification of the pi-bridge linking the donor and acceptor moieties is systematically explored, revealing the significant impact on the absorption, photocyclization, and relative stability of the open form. In particular, a position along the pi-bridge is found to be the most suited to redshift the absorption while preserving the cyclization. However, thermal back-reaction to the initial isomer is blocked. These effects are explained in terms of an increased acceptor capability offered by the pi-bridge substituent that can be modulated. This strategy opens the path toward derivatives with infra-red absorption and a potential anchoring point for further functionalization

Photoinduced Proton Transfer as a Possible Mechanism for Highly Efficient Excited-State Deactivation in Proteins

CASSCF//CASPT2 pathways for a two-glycine minimal model system show that photoinduced electron-driven forward and backward proton transfer could play an important role for the stability of proteins against damage by UV radiation, when a hydrogen bond is located between the two amino acids. The overall photoinduced process involves two electron and proton transfer processes (forward and backward) and results in the reformation of the initial closed-shell electronic structure of the system.Ministerio de Educación y CienciaUniversidad de Alcal

Chiral Hydrogen Bond Environment Providing Unidirectional Rotation in Photoactive Molecular Motors

Generation of a chiral hydrogen bond environment in efficient molecular photoswitches is proposed as a novel strategy for the design of photoactive molecular motors. Here, the following strategy is used to design a retinal-based motor presenting singular properties: (i) a single excitation wavelength is needed to complete the unidirectional rotation process (360°); (ii) the absence of any thermal step permits the process to take place at low temperatures; and (iii) the ultrafast process permits high rotational frequencies.Ministerio de Economía y CompetitividadMinisterio de Ciencia e InnovaciónUniversidad de Alcal

Thermodynamics of the interaction between spike protein of severe acute respiratory syndrome-coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 1000000 deaths all over the world and still lacks a medical treatment despite the attention of the whole scientific community. Human angiotensin-converting enzyme 2 (ACE2) was recently recognized as the transmembrane protein that serves as the point of entry of SARS-CoV-2 into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the protein complex. Moreover, the free energy of binding between ACE2 and the active receptor binding domain of the SARS-CoV-2 spike protein is evaluated quantitatively, providing for the first time the thermodynamics of virus?receptor recognition. Furthermore, the action of different ACE2 ligands is also examined in particular in their capacity to disrupt SARS-CoV-2 recognition, also providing via a free energy profile the quantification of the ligand-induced decreased affinity. These results improve our knowledge on molecular grounds of the SARS-CoV-2 infection and allow us to suggest rationales that could be useful for the subsequent wise molecular design for the treatment of COVID-19 cases

A biomimetic molecular switch at work: coupling photoisomerization dynamics to peptide structural rearrangement

In spite of considerable interest in the design of molecular switches towards photo-controllable (bio)materials, few studies focused on the major influence of the surrounding environment on the switch photoreactivities. We present a combined experimental and computational study of a retinal-like molecular switch linked to a peptide, elucidating the effects on the photoreactivity and on the a-helix secondary structure. Temperature-dependent, femtosecond UV-vis transient absorption spectroscopy and high-level hybrid quantum mechanics/molecular mechanics methods were applied to describe the photoisomerization process and the subsequent peptide rearrangement. It was found that the conformational heterogeneity of the ground state peptide controls the excited state potential energy surface and the thermally activated population decay. Still, a reversible a-helix to a-hairpin conformational change is predicted, paving the way for a fine photocontrol of different secondary structure elements, hence (bio)molecular functions, using retinal-inspired molecular switches

Structural Substituent Effect in the Excitation Energy of aChromophore: Quantitative Determination and Application toS-Nitrosothiols

A methodology for the prediction of excitation energies for substituted chromophores on the basis of ground state structures has been developed. The formalism introduces the concept of ?structural substituent excitation energy effect? for the rational prediction and quantification of the substituent effect in the excitation energy of a chromophore to an excited electronic state. This effect quantifies exclusively the excitation energy variation due to the structural changes of the chromophore induced by the substituent. Therefore, excitation bathochromic and hypsochromic shifts of substituted chromophores can be predicted on the basis of known ground and excited potential energy surfaces of a reference unsubstituted chromophore, together with the ground state minimum energy structure of the substituted chromophore. This formalism can be applied if the chemical substitution does not affect the nature of the electronic excitation, where the substituent effect can be understood as a force acting on the chromophore and provoking a structural change on it. The developed formalism provides a useful tool for quantitative and qualitative determination of the excitation energy of substituted chromophores and also for the analysis and determination of the structural changes affecting this energy. The proposed methodology has been applied to the prediction of the excitation energy to the first bright state of several S-nitrosothiols using the potential energy surfaces of methyl-S-nitrosothiol as a reference unsubstituted chromophore.Ministerio de Ciencia e InnovaciónUniversidad de Alcal

Active site structure and absorption spectrum of channelrhodopsin-2 wild-type and C128T mutant

In spite of considerable interest, the active site of channelrhodopsin still lacks a detailed atomistic description, the understanding of which could strongly enhance the development of novel optogenetics tools. We present a computational study combining different state-of-the-art techniques, including hybrid quantum mechanics/molecular mechanics schemes and high-level quantum chemical methods, to properly describe the hydrogen-bonding pattern between the retinal chromophore and its counterions in channelrhodopsin-2 Wild-Type and C128T mutant. Especially, we show by extensive ground state dynamics that the active site, containing a glutamic acid (E123) and a water molecule, is highly dynamic, sampling three different hydrogen-bonding patterns. This results in a broad absorption spectrum that is representative of the different structural motifs found. A comparison with bacteriorhodopsin, characterized by a pentagonal hydrogen-bonded active site structure, elucidates their different absorption properties