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 case.

Effect of the QM Size, Basis Set, and Polarization on QM/MM Interaction Energy Decomposition Analysis.

Herein, an Energy Decomposition Analysis (EDA) scheme extended to the framework of QM/MM calculations in the context of electrostatic embeddings (QM/MM-EDA) including atomic charges and dipoles is applied to assess the effect of the QM region size on the convergence of the different interaction energy components, namely, electrostatic, Pauli, and polarization, for cationic, anionic, and neutral systems interacting with a strong polar environment (water). Significant improvements are found when the bulk solvent environment is described by a MM potential in the EDA scheme as compared to pure QM calculations that neglect bulk solvation. The predominant electrostatic interaction requires sizable QM regions. The results reported here show that it is necessary to include a surprisingly large number of water molecules in the QM region to obtain converged values for this energy term, contrary to most cluster models often employed in the literature. Both the improvement of the QM wave function by means of a larger basis set and the introduction of polarization into the MM region through a polarizable force field do not translate to a faster convergence with the QM region size, but they lead to better results for the different interaction energy components. The results obtained in this work provide insight into the effect of each energy component on the convergence of the solute-solvent interaction energy with the QM region size. This information can be used to improve the MM FFs and embedding schemes employed in QM/MM calculations of solvated systems.

Automatic Rhodopsin Modeling with Multiple Protonation Microstates.

Automatic Rhodopsin Modeling (ARM) is a simulation protocol providing QM/MM models of rhodopsins capable of reproducing experimental electronic absorption and emission trends. Currently, ARM is restricted to a single protonation microstate for each rhodopsin model. Herein, we incorporate an extension of the minimal electrostatic model (MEM) into the ARM protocol to account for all relevant protonation microstates at a given pH. The new ARM+MEM protocol determines the most important microstates contributing to the description of the absorption spectrum. As a test case, we have applied this methodology to simulate the pH-dependent absorption spectrum of a toy model, showing that the single-microstate picture breaks down at certain pH values. Subsequently, we applied ARM+MEM toAnabaenasensory rhodopsin, confirming an improved description of its absorption spectrum when the titration of several key residues is considered.

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 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.

Deciphering the Chemical Basis of Fluorescence of a Selenium-Labeled Uracil Probe when Bound at the Bacterial Ribosomal A-Site.

We unveil in this work the main factors that govern the turn-on/off fluorescence of a Se-modified uracil probe at the ribosomal RNA A-site. Whereas the constraint into an "in-plane" conformation of the two rings of the fluorophore is the main driver for the observed turn-on fluorescence emission in the presence of the antibiotic paromomycin, the electrostatics of the environment plays a minor role during the emission process. Our computational strategy clearly indicates that, in the absence of paromomycin, the probe prefers conformations that show a dark S1 electronic state with participation of nπ* electronic transition contributions between the selenium atom and the π-system of the uracil moiety.

The Permeation Mechanism of Cisplatin Through a Dioleoylphosphocholine Bilayer*.

The investigation of the intermolecular interactions between platinum-based anticancer drugs and lipid bilayers is of special relevance to unveil the mechanisms involved in different steps of the anticancer mode of action of these drugs. We have simulated the permeation of cisplatin through a model membrane composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids by means of umbrella sampling classical molecular dynamics simulations. The initial physisorption of cisplatin into the polar region of the lipid membrane is controlled by long-range electrostatic interactions with the choline groups in a first step and, in a second step, by long-range electrostatic and hydrogen bond interactions with the phosphate groups. The second half of the permeation pathway, in which cisplatin diffuses through the nonpolar region of the bilayer, is characterized by the drop of the interactions with the polar heads and the rise of attractive interactions with the non-polar tails, which are dominated by van der Waals contributions. The permeation free-energy profile is explained by a complex balance between the drug/lipid interactions and the energy and entropy contributions associated with the dehydration of the drug along the permeation pathway and with the decrease and increase of the membrane ordering along the first and second half of the mechanism, respectively.

Characterization of cisplatin/membrane interactions by QM/MM energy decomposition analysis.

We extend for the first time a quantum mechanical energy decomposition analysis scheme based on deformation electron densities to a hybrid electrostatic embedding quantum mechanics/molecular mechanics framework. The implemented approach is applied to characterize the interactions between cisplatin and a dioleyl-phosphatidylcholine membrane, which play a key role in the permeation mechanism of the drug inside the cells. The interaction energy decomposition into electrostatic, induction, dispersion and Pauli repulsion contributions is performed for ensembles of geometries to account for conformational sampling. It is evidenced that the electrostatic and repulsive components are predominant in both polar and non-polar regions of the bilayer.

Binding of azobenzene and p-diaminoazobenzene to the human voltage-gated sodium channel Nav1.4.

The activity of voltage-gated ion channels can be controlled by the binding of photoswitches inside their internal cavity and subsequent light irradiation. We investigated the binding of azobenzene and p-diaminoazobenzene to the human Nav1.4 channel in the inactivated state by means of Gaussian accelerated molecular dynamics simulations and free-energy computations. Three stable binding pockets were identified for each of the two photoswitches. In all the cases, the binding is controlled by the balance between the favorable hydrophobic interactions of the ligands with the nonpolar residues of the protein and the unfavorable polar solvation energy. In addition, electrostatic interactions between the ligand and the polar aminoacids are also relevant for p-diaminoazobenzene due to the presence of the amino groups on the benzene moieties. These groups participate in hydrogen bonding in the most favorable binding pocket and in long-range electrostatic interactions in the other pockets. The thermodinamically preferred binding sites found for both photoswitches are close to the selectivity filter of the channel. Therefore, it is very likely that the binding of these ligands will induce alterations in the ion conduction through the channel.

Stacking Effects on Anthraquinone/DNA Charge-Transfer Electronically Excited States.

The design of more efficient photosensitizers is a matter of great importance in the field of cancer treatment by means of photodynamic therapy. One of the main processes involved in the activation of apoptosis in cancer cells is the oxidative stress on DNA once a photosensitizer is excited by light. As a consequence, it is very relevant to investigate in detail the binding modes of the chromophore with DNA, and the nature of the electronically excited states that participate in the induction of DNA damage, for example, charge-transfer states. In this work, we investigate the electronic structure of the anthraquinone photosensitizer intercalated into a double-stranded poly(dG-dC) decamer model of DNA. First, the different geometric configurations are analyzed by means of classical molecular dynamics simulations. Then, the excited states for the most relevant poses of anthraquinone inside the binding pocket are computed by an electrostatic-embedding quantum mechanics/molecular mechanics approach, where anthraquinone and one of the nearby guanine residues are described quantum mechanically to take into account intermolecular charge-transfer states. The excited states are characterized as monomer, exciton, excimer, and charge-transfer states based on the analysis of the transition density matrix, and each of these contributions to the total density of states and absorption spectrum is discussed in terms of the stacking interactions. These results are relevant as they represent the footing for future studies on the reactivity of anthraquinone derivatives with DNA and give insights on possible geometrical configurations that potentially favor the oxidative stress of DNA.

Attosecond impulsive stimulated X-ray Raman scattering in liquid water.

We report the measurement of impulsive stimulated x-ray Raman scattering in neutral liquid water. An attosecond pulse drives the excitations of an electronic wavepacket in water molecules. The process comprises two steps: a transition to core-excited states near the oxygen atoms accompanied by transition to valence-excited states. Thus, the wavepacket is impulsively created at a specific atomic site within a few hundred attoseconds through a nonlinear interaction between the water and the x-ray pulse. We observe this nonlinear signature in an intensity-dependent Stokes Raman sideband at 526 eV. Our measurements are supported by our state-of-the-art calculations based on the polarization response of water dimers in bulk solvation and propagation of attosecond x-ray pulses at liquid density.

On the Permeation of Polychlorinated Dibenzodioxins and Dibenzofurans through Lipid Membranes: Classical MD and Hybrid QM/MM-EDA Analysis.

The permeation of dioxin-like pollutants, namely, chlorinated dibenzodioxins and dibenzofurans, through lipid membranes has been simulated using classic molecular dynamics (CMD) combined with the umbrella sampling approach. The most toxic forms of chlorinated dibenzodioxin and dibenzofuran, 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDF), and a dioleyl-phosphatidylcholine (DOPC) lipid membrane of 50 Å wide have been chosen for our study. The free energy profile shows the penetration process is largely favoured thermodynamically (ΔG ≈ -12 kcal/mol), with a progressively decrease of the free energy until reaching the energy minima at distances of 8 Å and 9.5 Å from the centre of the membrane for, respectively, TCDD and TCDF. At the centre of the membrane, both molecules display subtle local maxima with free energy differences of 0.5 and 1 kcal/mol with respect to the energy minima for TCDD and TCDF, respectively. Furthermore, the intermolecular interactions between the molecules and the lipid membrane have been characterized at the minima and the local maxima using hybrid quantum mechanics/molecular mechanics energy decomposition analysis (QM/MM-EDA). Total interaction energies of -17.5 and -16.5 kcal/mol have been found at the energy minima for TCDD and TCDF, respectively. In both cases, the dispersion forces govern the molecule-membrane interactions, no significant changes have been found at the local maxima, in agreement with the classical free energy profile. The small differences found in the results obtained for TCDD and TCDF point out that the adsorption and diffusion processes through the cell membrane are not related to the different toxicity shown by these pollutants.

Activation by oxidation and ligand exchange in a molecular manganese vanadium oxide water oxidation catalyst.

Despite their technological importance for water splitting, the reaction mechanisms of most water oxidation catalysts (WOCs) are poorly understood. This paper combines theoretical and experimental methods to reveal mechanistic insights into the reactivity of the highly active molecular manganese vanadium oxide WOC [Mn4V4O17(OAc)3]3- in aqueous acetonitrile solutions. Using density functional theory together with electrochemistry and IR-spectroscopy, we propose a sequential three-step activation mechanism including a one-electron oxidation of the catalyst from [Mn2 3+Mn2 4+] to [Mn3+Mn3 4+], acetate-to-water ligand exchange, and a second one-electron oxidation from [Mn3+Mn3 4+] to [Mn4 4+]. Analysis of several plausible ligand exchange pathways shows that nucleophilic attack of water molecules along the Jahn-Teller axis of the Mn3+ centers leads to significantly lower activation barriers compared with attack at Mn4+ centers. Deprotonation of one water ligand by the leaving acetate group leads to the formation of the activated species [Mn4V4O17(OAc)2(H2O)(OH)]- featuring one H2O and one OH ligand. Redox potentials based on the computed intermediates are in excellent agreement with electrochemical measurements at various solvent compositions. This intricate interplay between redox chemistry and ligand exchange controls the formation of the catalytically active species. These results provide key reactivity information essential to further study bio-inspired molecular WOCs and solid-state manganese oxide catalysts.

Percutaneous retrograde revascularization of the superior mesenteric artery via the celiac artery for chronic mesenteric ischemia.

An elderly woman developed chronic mesenteric ischemia (CMI) due to severe stenosis of the celiac artery and chronic total occlusion of the superior mesenteric artery (SMA). Stenting of the celiac artery resulted in resolution of CMI, but symptoms recurred 4 months later due to restenosis. We report successful sustained resolution of CMI after percutaneous retrograde revascularization of the SMA via the celiac artery.

The importance of recognizing and treating low levels of high-density lipoprotein cholesterol: a new era in atherosclerosis management.

Low levels of high-density lipoprotein cholesterol (HDL-C) represent a major cardiovascular risk factor, with a stronger relationship to coronary heart disease than that seen with elevated levels of low-density lipoprotein cholesterol (LDL-C). HDL-C has important antiatherogenic effects, including reverse cholesterol transport, inhibition of LDL-C oxidation, and antiplatelet and anti-inflammatory actions. Patients with low HDL-C are also at an amplified risk of coronary heart disease due to the common coexistence of other risk factors, including excess adiposity, metabolic syndrome, type 2 diabetes mellitus, hypertriglyceridemia, and the atherogenic dyslipidemia characterized by small dense LDL-C. First-line therapy of low HDL-C generally consists of nonpharmacologic measures such as improved fitness and weight loss. Current pharmaceutical options include statins, fibrates, and nicotinic acid. A host of novel approaches involving HDL-C and reverse cholesterol transport hold the promise of fundamentally changing the natural history of atherosclerosis, the most common and important chronic disease in humans.

Spontaneous coronary artery dissection.

A 45-year-old female athlete with no history of cardiovascular disease or coronary risk factors presented with a non-ST-segment elevation myocardial infarction due to spontaneous right coronary artery dissection. She was treated medically with resolution of her symptoms. Repeat angiography due to recurrent exertional chest discomfort showed TIMI-3 flow and no evidence of dissection. Intravascular ultrasound documented discrete areas of resolving hematoma, but no dissection flap or impingement of the lumen >30%. A coronary computed tomography 6 months later revealed absence of any vascular abnormalities. This rare but potentially lethal condition should be considered in the differential diagnosis of young patients with chest pain, myocardial infarction, or sudden cardiac death, especially if it involves women either in the peripartum period or those using oral contraceptives, or patients without evidence of coronary atherosclerosis or traditional cardiovascular risk factors.

Disparate effects of left ventricular geometry and obesity on mortality in patients with preserved left ventricular ejection fraction.

Left ventricular (LV) geometry predicts cardiovascular events. Although obesity is a risk factor for cardiovascular diseases, studies have noted a paradox regarding obesity and prognosis. To our knowledge no studies have determined the impact of obesity on LV geometry as well as mortality in patients with preserved ejection fraction. We evaluated 30,920 patients with preserved ejection fraction, including 11,792 obese patients as well as 19,128 nonobese patients to determine the impact of 4 LV geometric patterns, including normal structure, concentric remodeling (CR), as well as eccentric or concentric hypertrophy and obesity on mortality during an average follow-up of 3.2 +/- 1.4 years. Abnormal LV geometry occurred more commonly in obese than nonobese patients (49% vs 44%, p <0.0001 for the difference in the 4 patterns). In obese patients, CR was the most prevalent abnormal pattern (34%), with eccentric and concentric LV hypertrophy occurring in 7% and 8%, respectively, compared with nonobese patients (32%, 6%, and 6%, respectively). Overall mortality was considerably lower in obese than nonobese (3.9% vs 6.5%, p <0.0001). In both groups, progressive increases in mortality compared with normal structure occurred with CR, eccentric and concentric LV hypertrophy (obese patients 2.8%, 4.8%, 5.3%, and 6.9%, respectively; and nonobese patients 4.3%, 8.4%, 9.6%, and 11.8%, respectively). In conclusion, although an obesity paradox exists, in that obesity is associated with higher prevalence of structural abnormalities but lower mortality than in nonobese patients, our data demonstrate that LV geometric abnormalities are prevalent in both obese and nonobese patients with normal ejection fraction and are associated with progressive increases in mortality.

Gender-Dependent Association of FTO Polymorphisms with Body Mass Index in Mexicans.

To evaluate the associations between six single-nucleotide polymorphisms (SNPs) in intron 1 of FTO and body mass index (BMI), a case-control association study of 2314 unrelated Mexican-Mestizo adult subjects was performed. The association between each SNP and BMI was tested using logistic and linear regression adjusted for age, gender, and ancestry and assuming additive, recessive, and dominant effects of the minor allele. Association analysis after BMI stratification showed that all five FTO SNPs (rs1121980, rs17817449, rs3751812, rs9930506, and rs17817449), were significantly associated with obesity class II/III under an additive model (P<0.05). Interestingly, we also documented a genetic model-dependent influence of gender on the effect of FTO variants on increased BMI. Two SNPs were specifically associated in males under a dominant model, while the remainder were associated with females under additive and recessive models (P<0.05). The SNP rs9930506 showed the highest increased in obesity risk in females (odds ratio = 4.4). Linear regression using BMI as a continuous trait also revealed differential FTO SNP contributions. Homozygous individuals for the risk alleles of rs17817449, rs3751812, and rs9930506 were on average 2.18 kg/m(2) heavier than homozygous for the wild-type alleles; rs1121980 and rs8044769 showed significant but less-strong effects on BMI (1.54 kg/m(2) and 0.9 kg/m(2), respectively). Remarkably, rs9930506 also exhibited positive interactions with age and BMI in a gender-dependent manner. Women carrying the minor allele of this variant have a significant increase in BMI by year (0.42 kg/m(2), P = 1.17 x 10(-10)). Linear regression haplotype analysis under an additive model, confirmed that the TGTGC haplotype harboring all five minor alleles, increased the BMI of carriers by 2.36 kg/m(2) (P = 1.15 x 10(-5)). Our data suggest that FTO SNPs make differential contributions to obesity risk and support the hypothesis that gender differences in the mechanisms involving these variants may contribute to disease development.

Risk of anaphylaxis after reexposure to intravenous lepirudin in patients with current or past heparin-induced thrombocytopenia.

OBJECTIVE: To retrospectively assess the signs and symptoms indicative of adverse reactions to repeated exposures to lepirudin in patients with heparin-induced thrombocytopenia who received at least 2 courses of lepirudin therapy. PATIENTS AND METHODS: Medical records were retrospectively assessed from adult patients who received at least 2 courses of lepirudin therapy separated by at least 1 week between January 1999 and June 2002 at The Cleveland Clinic, Cleveland, Ohio. We evaluated the list of 289 low-level terms for possible signs and symptoms of anaphylactic reactions In the medical dictionary for regulatory activities as well as patient vital signs to detect manifestations of immediate hypersensitivity reactions. Vital signs from the day before initiation of lepirudin therapy were compared with those from days 1 and 2 after exposure. RESULTS: No cases of anaphylaxis or allergic reaction related to lepirudin administration were identified among 43 adult patients. On day 1 of lepirudin, 10 patients had lower systolic blood pressures (by > or =20 mm Hg) than pre-lepirudin values, and 4 patients had systolic blood pressures of less than 100 mm Hg. CONCLUSIONS: Isolated asymptomatic decreases in blood pressure after patient reexposure to lepirudin most likely do not reflect anaphylaxis due to lepirudin. We believe that isolated and uncommon cases of anaphylaxis temporally related to lepirudin exposure should not preclude its use in patients with heparin-induced thrombocytopenia and past lepirudin exposure.

Amiodarone induced thyrotoxicosis: diagnostic and therapeutic strategies.

Amiodarone causes thyrotoxicosis in 3% of US patients who use it. Two types of amiodarone-induced thyrotoxicosis are recognized, designated type 1 and type 2, based on whether or not the patient had a preexisting thyroid disorder. Distinguishing between the two can be difficult, but it is important for providing appropriate therapy promptly.

Effects of left ventricular geometry and obesity on mortality in women with normal ejection fraction.

Left ventricular (LV) geometry is an independent predictor of cardiovascular morbidity and mortality. Although obesity is a known risk factor for cardiovascular diseases, studies have suggested a paradoxical relation between obesity and prognosis. We retrospectively assessed 26,126 female patients with normal LV ejection fraction to determine the impact of LV geometry, including normal structure, concentric remodeling, and eccentric or concentric LV hypertrophy, and obesity on mortality during an average follow-up of 1.7 years. Abnormal LV geometry occurred more commonly in obese (body mass index ≥30 kg/m(2), n = 10,465) compared with nonobese (body mass index <30 kg/m(2), n = 15,661) patients (56% vs 47%, respectively, p <0.0001). Overall mortality, however, was considerably less in obese compared with nonobese patients (5.6% vs 8.7%, respectively, p <0.0001). In both groups, progressive increases in mortality were observed from normal structure to concentric remodeling and then to eccentric and concentric LV hypertrophy (obese patients 2.9%, 6.5%, 6.7%, and 11.1%, respectively, and nonobese patients 5.3%, 10.6%, 11.4%, and 16.8%, respectively, p <0.0001 for trend). In conclusion, although an obesity paradox exists, in that obesity in women is associated with abnormal LV geometry but less mortality, our data demonstrate that abnormal LV geometric patterns are highly prevalent in both obese and nonobese female patients with normal ejection fraction and are associated with greater mortality.