MoBioTools: a toolkit to setup quantum mechanics/molecular mechanics calculations

We present a toolkit that allows for the preparation of QM/MM input files from a conformational ensemble of molecular geometries. The package is currently compatible with trajectory and topology files in Amber, CHARMM, GROMACS and NAMD formats, and has the possibility to generate QM/MM input files for Gaussian (09 and 16), Orca (≥4.0), NWChem and (Open)Molcas. The toolkit can be used in command line, so that no programming experience is required, although it presents some features that can also be employed as a python application programming interface. We apply the toolkit in four situations in which different electronic-structure properties of organic molecules in the presence of a solvent or a complex biological environment are computed: the reduction potential of the nucleobases in acetonitrile, an energy decomposition analysis of tyrosine interacting with water, the absorption spectrum of an azobenzene derivative integrated into a voltage-gated ion channel, and the absorption and emission spectra of the luciferine/luciferase complex. These examples show that the toolkit can be employed in a manifold of situations for both the electronic ground state and electronically excited states. It also allows for the automatic correction of the active space in the case of CASSCF calculations on an ensemble of geometries, as it is shown for the azobenzene derivative photoswitch caseSpanish Ministry of Science and Innovation; MCIN/AEI, Grant/Award Numbers: PID2020-117806GA-I00, PID2019-110091GB-I00; María de Maeztu, Grant/Award Number: CEX2018-000805-M; Comunidad de Madrid, Grant/Award Number: 2018-T1/BMD-10261; Xunta de Galicia, Grant/Award Number: GRC2019/24; the European Social Fund; Spanish Ministry of Education and Vocational Training, Grant/Award Number: FPU19/02292; Universidade de Vigo, Grant/Award Number: PREUVIGO-21; Universidad Autonoma de Madri

Free triiodothyronine levels and age influences the metabolic profile and COVID-19 severity parameters in euthyroid and levothyroxine-treated patients

Metabolic reprogramming is required to fight infections and thyroid hormones are key regulators of metabolism. We have analyzed in hospitalized COVID-19 patients: 40 euthyroid and 39 levothyroxine (LT4)-treated patients in the ward and 29 euthyroid and 9 LT4-treated patients in the intensive care unit (ICU), the baseline characteristics, laboratory data, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3/FT4 ratio, 11 antiviral cytokines and 74 metabolomic parameters. No evidence for significant differences between euthyroid and LT4-treated patients were found in the biochemical, metabolomic and cytokines parameters analyzed. Only TSH (p=0.009) and ferritin (p=0.031) showed significant differences between euthyroid and LT4-treated patients in the ward, and TSH (p=0.044) and FT4 (p=0.012) in the ICU. Accordingly, severity and mortality were similar in euthyroid and LT4-treated patients. On the other hand, FT3 was negatively related to age (p=0.012), independently of sex and body mass index in hospitalized COVID-19 patients. Patients with low FT3 and older age showed a worse prognosis and higher levels of the COVID-19 severity markers IL-6 and IL-10 than patients with high FT3. IL-6 negatively correlated with FT3 (p=0.023) independently of age, body mass index and sex, whereas IL-10 positively associated with age (p=0.035) independently of FT3, body mass index and sex. A metabolomic cluster of 6 parameters defined low FT3 ward patients. Two parameters, esterified cholesterol (p=4.1x10) and small HDL particles (p=6.0x10) correlated with FT3 independently of age, body mass index and sex, whereas 3-hydroxybutyrate (p=0.010), acetone (p=0.076), creatinine (p=0.017) and high-density-lipoprotein (HDL) diameter (p=8.3x10) were associated to FT3 and also to age, with p-values of 0.030, 0.026, 0.017 and 8.3x10, respectively. In conclusion, no significant differences in FT3, cytokines, and metabolomic profile, or in severity and outcome of COVID-19, were found during hospitalization between euthyroid patients and hypothyroid patients treated with LT4. In addition, FT3 and age negatively correlate in COVID-19 patients and parameters that predict poor prognosis were associated with low FT3, and/or with age. A metabolomic cluster indicative of a high ketogenic profile defines non-critical hospitalized patients with low FT3 levels.PID2020-116146RB-I00 from the Ministerio de Ciencia e Innovación with European Regional Development Funds (FEDER), BMD-3724 from the Comunidad de Madrid, 202020E169 from the CSIC, 2020PANDE00082 from the Generalitad de Cataluña and Fundación Hay Esperanza

Computation of Oxidation Potentials of Solvated Nucleobases by Static and Dynamic Multilayer Approaches

The determination of the redox properties of nucleobases is of paramount importance to get insight into the charge-transfer processes in which they are involved, such as those occurring in DNA-inspired biosensors. Although many theoretical and experimental studies have been conducted, the value of the one-electron oxidation potentials of nucleobases is not welldefined. Moreover, the most appropriate theoretical protocol to model the redox properties has not been established yet. In this work, we have implemented and evaluated different static and dynamic approaches to compute the one-electron oxidation potentials of solvated nucleobases. In the static framework, two thermodynamic cycles have been tested to assess their accuracy against the direct determination of oxidation potentials from the adiabatic ionization energies. Then, the introduction of vibrational sampling, the effect of implicit and explicit solvation models, and the application of the Marcus theory have been analyzed through dynamic methods. The results revealed that the static direct determination provides more accurate results than thermodynamic cycles. Moreover, the effect of sampling has not shown to be relevant, and the results are improved within the dynamic framework when the Marcus theory is applied, especially in explicit solvent, with respect to the direct approach. Finally, the presence of different tautomers in water does not affect significantly the one-electron oxidation potentialsWe acknowledge the generous allocation of computer time at the Centro de Computación Científica at the Universidad Autónoma de Madrid (CCC-UAM). This work was partially supported by the MICINN, Spanish Ministry of Science and Innovation, Projects PID2019-110091GB-I00 and PID2020- 117806GA-I00 funded by MCIN/AEI/10.13039/ 501100011033, and the “María de Maeztu” (CEX2018- 000805-M) Program for Centers of Excellence in R&D. J.J.N. and G.C. acknowledge the Comunidad de Madrid for funding through the Attraction of Talent Program (Grant ref 2018-T1/BMD-10261). N.A.O. acknowledges the Comunidad de Madrid and European Social Fund for funding through the Programa Operativo de Empleo Juvenil y la Iniciativa de Empleo Juvenil. J.L.T. acknowledges the FPU19/02292 grant from the Spanish Ministry of Education and Vocational Trainin

Light-Induced Control of Voltage Gated Ion Channels

Voltage gated ion channels are transmembrane proteins responsible for the generation and propagation of action potentials in excitable cells. They are key targets in receptor pharmacology, since the simple actions of opening and closing their pore with different kinetics or conductivity have been associated with a large number of channelopaties. Crystal structures of ion channels became available only in the last decades and, in combination with mutagenesis data, allowed the identification of drugs able to modulate ion conduction. However, most of the traditional modulators are not selective and present adverse side effects. Photopharmacology is establishing a new approach to overcome the problem of selectivity often present in voltage gated ion channels due to highly conserved binding regions among channels of the same subfamily. In this review, we describe the central pore region of Voltage gated sodium and potassium channels from a structural and pharmacological perspective, characterizing the binding mode of natural toxins and synthetic compounds able to physically occlude ion conduction. In addition, a bridge is created between classical pharmacology and photopharmacology, describing the approaches aimed to control the activity of voltage gated ion channels by photosensitive drugs

Computation of Oxidation Potentials of Solvated Nucleobases by Static and Dynamic Multilayer Approaches

The determination of the redox properties of nucleobases is of paramount importance to get insight into the charge-transfer processes in which they are involved, as those occurring in DNA-inspired biosensors. Although many theoretical and experimental studies have been conducted, the value of the one-electron oxidation potentials of nucleobases is not well defined. Moreover, the most appropriate theoretical protocol to model the redox properties has not been established yet. In this work, we have implemented and evaluated different static and dynamic approaches to compute the one-electron oxidation potentials of solvated nucleobases. In the static framework, two thermodynamic cycles have been tested to assess their accuracy against the direct determination of oxidation potentials from the adiabatic ionization energies. Then, the introduction of vibrational sampling, the effect of implicit and explicit solvation models, and the application of the Marcus theory have been analyzed through dynamic methods. The results revealed that the static direct determination provides more accurate results than thermodynamic cycles. Moreover, the effect of sampling has not shown to be relevant, and the results are improved within the dynamic framework when the Marcus theory is applied, especially in explicit solvent, with respect to the direct approach. Finally, the presence of different tautomers in water does not affect significantly the one-electron oxidation potentials

MoBioTools: A Toolkit to Setup QM/MM Calculations

We present a toolkit that allows for the preparation of QM/MM input files from a conformational ensemble of molecular geometries. The toolkit can be used in command line, so that no programming experience is required, although it presents some features that can also be employed as a python application programming interface. We apply the toolkit in four situations in which different electronic-structure properties of organic molecules in the presence of a solvent or a complex biological environment are computed: the reduction potential of the nucleobases in acetonitrile, an energy decomposition analysis of tyrosine interacting with water, the absorption spectrum of an azobenzene derivative integrated into a voltage-gated ion channel, and the absorption and emission spectra of the luciferine/luciferase complex. These examples show that the toolkit can be employed in a manifold of situations for both the electronic ground state and electronically excited states. It also allows for the automatic correction of the active space in the case of CASSCF calculations on an ensemble of geometries, as it is shown for the azobenzene derivative photoswitch case