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Specialized computational chemistry packages have permanently reshaped the landscape of chemical and materials science by providing tools to support and guide experimental efforts and for the prediction of atomistic and electronic properties. In this regard, electronic structure packages have played a special role by using first-principle-driven methodologies to model complex chemical and materials processes. Over the past few decades, the rapid development of computing technologies and the tremendous increase in computational power have offered a unique chance to study complex transformations using sophisticated and predictive many-body techniques that describe correlated behavior of electrons in molecular and condensed phase systems at different levels of theory. In enabling these simulations, novel parallel algorithms have been able to take advantage of computational resources to address the polynomial scaling of electronic structure methods. In this paper, we briefly review the NWChem computational chemistry suite, including its history, design principles, parallel tools, current capabilities, outreach, and outlook.

Accurate ab initio intermolecular potential energy surfaces (IPES) have been obtained for the first time for the ground electronic state of the C2H2–Kr and C2H2–Xe van der Waals complexes. Extensive tests, including complete basis set and all-electron scalar relativistic results, support their calculation at the CCSD(T) level of theory, using small-core relativistic pseudopotentials for the rare-gas atoms and aug-cc-pVQZ basis sets extended with a set of 3s3p2d1f1g mid-bond functions. All results are corrected for the basis set superposition error. The importance of the scalar relativistic and rare-gas outer-core (n–1)d correlation effects is investigated. The calculated IPES, adjusted to analytical functions, are characterized by global minima corresponding to skew T-shaped geometries, in which the Jacobi vector positioning the rare-gas atom with respect to the center of mass of the C2H2 moiety corresponds to distances of 4.064 and 4.229 Å, and angles of 65.22° and 68.67° for C2H2–Kr and C2H2–Xe, respectively. The interaction energy of both complexes is estimated to be −151.88 (1.817 kJ mol−1) and −182.76 cm−1 (2.186 kJ mol−1), respectively. The evolution of the topology of the IPES as a function of the rare-gas atom, from He to Xe, is also discussed. [ABSTRACT FROM AUTHOR]

Artificial Intelligence (AI) is already a reality in health systems, bringing benefits to patients, healthcare providers, and other stakeholders in the health care. To further leverage AI in health, Belgium is advised to make policy-level decisions about how to fund, design and undertake actions focussing on data access and inclusion, IT-infrastructure, legal and ethical frameworks, public and professional trust, in addition to education and interpretation. EU initiatives, such as European Health data space (EHDS), the Genomics Data Infrastructure (GDI) and the EU Cancer Imaging Infrastructure (EUCAIM) are building EU data infrastructures. To continue these positive developments, Belgium should continue to invest and support existing European data infrastructures. At the national level, a clear vision and strategy need to be developed and infrastructures need to be harmonized at the European level., (© 2024. The Author(s).)

Background: Precision medicine represents a paradigm shift in health systems, moving from a one-size-fits-all approach to a more individualized form of care, spanning multiple scientific disciplines including drug discovery, genomics, and health communication. This study aims to explore the contextual factors influencing the equitable implementation of precision medicine in Belgium for incorporating precision medicine into routine cancer care within the Belgian health system., Methods: As part of a foresight study, our approach evaluates critical factors affecting the implementation of precision oncology. The study scrutinizes contextual, i.e. demographic, economic, societal, technological, environmental, and political/policy-related (DESTEP) factors, identified through a comprehensive literature review and validated by a multidisciplinary group at the Belgian Cancer Center, Sciensano. An expert survey further assesses the importance and likelihood of these factors, illuminating potential barriers and facilitators to implementation., Results: Based on the expert survey, five key elements (rising cancer rates, dedicated healthcare reimbursement budgets, increasing healthcare expenditures, advanced information technology solutions for data transfer, and demand for high-quality data) are expected to influence the equitable implementation of precision medicine in routine cancer care in Belgium in the future., Conclusions: This work contributes to the knowledge base on precision medicine in Belgium and public health foresight, exploring the implementation challenges and suggesting solutions with an emphasis on the importance of comparative analyses of health systems, evaluation of health technology assessment methods, and the exploration of ethical issues in data privacy and equity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)

The synthesis of eight Ru(II) and Os(II) photosensitizers bearing a common 9,10-disubstituted-1,4,5,8-tetraazaphenanthrene backbone is reported. With Os(II) photosensitizers, the 9,10-diNH 2 -1,4,5,8-tetraazaphenanthrene could be directly chelated onto the metal center via the heteroaromatic moiety, whereas similar conditions using Ru(II) resulted in the formation of an o -quinonediimine derivative. Hence, an alternative route, proceeding via the chelation of 9-NH 2 -10-NO 2 -1,4,5,8-tetraazaphenanthrene and subsequent ligand reduction of the corresponding photosensitizers was developed. Photosensitizers chelated via the polypyridyl-type moiety exhibited classical photophysical properties whereas the o -quinonediimine chelated Ru(II) analogues exhibited red-shifted absorption (520 nm) and no photoluminescence at room temperature in acetonitrile. The most promising photosensitizers were investigated for excited-state quenching with guanosine-5'-monophosphate in aqueous buffered conditions where reductive excited-state electron transfer was observed by nanosecond transient absorption spectroscopy.

Genomic medicine has great potential to offer insights into how humans' genetic variation can affect their health, prevention options and treatment responses. The Beyond 1 Million Genomes (B1MG) project was kicked off in 2020 with the aim of building a federated network of genomic data in Europe, in which Belgium took part as a piloting country. B1MG developed a framework to enable all interested countries to self-evaluate the level of maturity of national genomic medicine practices following a common matrix, called Maturity Level Model (MLM), that contained 49 indicators across eight domains: I. Governance and strategy; II. Investment and economic model; III. Ethics, legislation and policy; IV. Public awareness and acceptance; V. Workforce skills and organisation; VI. Clinical organisation, infrastructure and tools; VII. Clinical genomics guidelines and infrastructure; and VIII. Data management, standards and infrastructure. The ongoing Genomic Data Infrastructure (GDI) project aims to capitalise on the experience of B1MG piloting countries and their MLM results. In this paper, we present the qualitative and quantitative outcomes of B1MG MLM assessment in Belgium and discuss their relevance to GDI. The insights gained from this study can be helpful for steering future policy directions and interventions on genomics in Belgium and beyond., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

We investigated effectiveness of (1) mRNA booster vaccination versus primary vaccination only and (2) heterologous (viral vector-mRNA) versus homologous (mRNA-mRNA) prime-boost vaccination against severe outcomes of BA.1, BA.2, BA.4 or BA.5 Omicron infection (confirmed by whole genome sequencing) among hospitalized COVID-19 patients using observational data from national COVID-19 registries. In addition, it was investigated whether the difference between the heterologous and homologous prime-boost vaccination was homogenous across Omicron sub-lineages. Regression standardization (parametric g-formula) was used to estimate counterfactual risks for severe COVID-19 (combination of severity indicators), intensive care unit (ICU) admission, and in-hospital mortality under exposure to different vaccination schedules. The estimated risk for severe COVID-19 and in-hospital mortality was significantly lower with an mRNA booster vaccination as compared to only a primary vaccination schedule (RR = 0.59 [0.33; 0.85] and RR = 0.47 [0.15; 0.79], respectively). No significance difference was observed in the estimated risk for severe COVID-19, ICU admission and in-hospital mortality with a heterologous compared to a homologous prime-boost vaccination schedule, and this difference was not significantly modified by the Omicron sub-lineage. Our results support evidence that mRNA booster vaccination reduced the risk of severe COVID-19 disease during the Omicron-predominant period.

Background: Differences in the genetic material of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants may result in altered virulence characteristics. Assessing the disease severity caused by newly emerging variants is essential to estimate their impact on public health. However, causally inferring the intrinsic severity of infection with variants using observational data is a challenging process on which guidance is still limited. We describe potential limitations and biases that researchers are confronted with and evaluate different methodological approaches to study the severity of infection with SARS-CoV-2 variants., Methods: We reviewed the literature to identify limitations and potential biases in methods used to study the severity of infection with a particular variant. The impact of different methodological choices is illustrated by using real-world data of Belgian hospitalized COVID-19 patients., Results: We observed different ways of defining coronavirus disease 2019 (COVID-19) disease severity (e.g., admission to the hospital or intensive care unit versus the occurrence of severe complications or death) and exposure to a variant (e.g., linkage of the sequencing or genotyping result with the patient data through a unique identifier versus categorization of patients based on time periods). Different potential selection biases (e.g., overcontrol bias, endogenous selection bias, sample truncation bias) and factors fluctuating over time (e.g., medical expertise and therapeutic strategies, vaccination coverage and natural immunity, pressure on the healthcare system, affected population groups) according to the successive waves of COVID-19, dominated by different variants, were identified. Using data of Belgian hospitalized COVID-19 patients, we were able to document (i) the robustness of the analyses when using different variant exposure ascertainment methods, (ii) indications of the presence of selection bias and (iii) how important confounding variables are fluctuating over time., Conclusions: When estimating the unbiased marginal effect of SARS-CoV-2 variants on the severity of infection, different strategies can be used and different assumptions can be made, potentially leading to different conclusions. We propose four best practices to identify and reduce potential bias introduced by the study design, the data analysis approach, and the features of the underlying surveillance strategies and data infrastructure., (© 2022. The Author(s).)

Two new cyclometalated Ir(III) diimine complexes were used as photosensitizers for homogeneous hydrogen evolution reaction (HER). These complexes were characterized by electrochemistry, ultraviolet-visible absorption, time-resolved and steady-state photoluminescence spectroscopy as well as by theoretical methods. The metal-ligand-to-ligand charge transfer character of their lowest excited state was shown to be competent for efficient H 2 photoproduction in the presence of [Co(dmgH) 2 (py)Cl] as the hydrogen evolution catalyst, triethanolamine as the sacrificial electron donor, and HBF 4 as the proton source. Under optimized experimental conditions, both complexes displayed HER over a period of more than 90 h, with turnover numbers reaching up to 11,650, 10,600, and 174 mol H2 mol PS -1 under blue-, green-, and red-light irradiation, respectively. Both complexes showed higher stability and efficiency vs HER than most of the previously described systems of the same kind.

Efficient excited-state electron transfer between an iron(III) photosensitizer and organic electron donors was realized with green light irradiation. This advance was enabled by the use of the previously reported iron photosensitizer, [Fe(phtmeimb) 2 ] + (phtmeimb = {phenyl[tris(3-methyl-imidazolin-2-ylidene)]borate}, that exhibited long-lived and luminescent ligand-to-metal charge-transfer (LMCT) excited states. A benchmark dehalogenation reaction was investigated with yields that exceed 90% and an enhanced stability relative to the prototypical photosensitizer [Ru(bpy) 3 ] 2+ . The initial catalytic step is electron transfer from an amine to the photoexcited iron sensitizer, which is shown to occur with a large cage-escape yield. For LMCT excited states, this reductive electron transfer is vectorial and may be a general advantage of Fe(III) photosensitizers. In-depth time-resolved spectroscopic methods, including transient absorption characterization from the ultraviolet to the infrared regions, provided a quantitative description of the catalytic mechanism with associated rate constants and yields.

A detailed photophysical investigation of two dinuclear ruthenium(ii) complexes is reported. The two metallic centers were coordinated to a bis-2,2'-bipyridine bridging ligand, connected either through the para (Lp, Dp) or the meta position (Lm, Dm). The results obtained herein were compared to the prototypical [Ru(bpy)3]2+ parent compound. The formation of dinuclear complexes was accompanied by the expected increase in molar absorption coefficients, i.e. 12 000 M-1 cm-1, 17 000 M-1 cm-1, and 22 000 M-1 cm-1 at the lowest energy MLCTmax transition for [Ru(bpy)3]2+, Dm and Dp respectively. The Lp bridging ligand resulted in a ruthenium(ii) dinuclear complex that absorbed more visible light, and had a longer-lived and more delocalized excited-state compared to a complex with the Lm bridging ligand. Variable temperature measurements provided valuable information about activation energies to the uppermost 3MLCT state and the metal-centered (3MC) state, often accompanied by irreversible ligand-loss chemistry. At 298 K, 48% of [Ru(bpy)3]2+* excited-state underwent deactivation through the 3MC state, whereas this deactivation pathway remained practically unpopulated (<0.5%) in both dinuclear complexes.

The excited-state quenching of [Ru(TAP) 2 (HAT)] 2+ (TAP = 1,4,5,8-tetraazaphenanthrene, HAT= 1,4,5,8,9,12-hexaazatriphenylene) by hydroquinone (H 2 Q), N-acetyl-tyrosine (N-Ac-Tyr) or guanosine-5'-monophosphate (GMP) was investigated at various pH values. The quenching occurs via electron/proton transfer, as evidenced by transient absorption spectroscopy and confirmed by 1 H photochemically induced dynamic nuclear polarization (photo-CIDNP). Reductive quenching also occurs in strongly acidic solution despite a much shorter lifetime of the protonated excited-state complex. Photo-CIDNP revealed a different mechanism at low pH, involving protonation before electron transfer and yielding a distinct protonated monoreduced complex. The experimental photo-CIDNP patterns are consistent with density functional theory calculations. This work highlights the power of 1 H photo-CIDNP for characterizing, at the atomic level, transient species involved in electron-transfer processes.

Acute viral infections pose many practical challenges for the accurate assessment of the impact of novel therapies on viral growth and decay. Using the example of influenza A, we illustrate how the measurement of infection-related quantities that determine the dynamics of viral load within the human host, can inform investigators on the course and severity of infection and the efficacy of a novel treatment. We estimated the values of key infection-related quantities that determine the course of natural infection from viral load data, using Markov Chain Monte Carlo methods. The data were placebo group viral load measurements collected during volunteer challenge studies, conducted by Roche, as part of the oseltamivir trials. We calculated the values of the quantities for each patient and the correlations between the quantities, symptom severity and body temperature. The greatest variation among individuals occurred in the viral load peak and area under the viral load curve. Total symptom severity correlated positively with the basic reproductive number. The most sensitive endpoint for therapeutic trials with the goal to cure patients is the duration of infection. We suggest laboratory experiments to obtain more precise estimates of virological quantities that can supplement clinical endpoint measurements.

Background: About 90% of drugs fail in clinical development. The question is whether trials fail because of insufficient efficacy of the new treatment, or rather because of poor trial design that is unable to detect the true efficacy. The variance of the measured endpoints is a major, largely underestimated source of uncertainty in clinical trial design, particularly in acute viral infections. We use a clinical trial simulator to demonstrate how a thorough consideration of the variability inherent in clinical trials of novel therapies for acute viral infections can improve trial design., Methods and Findings: We developed a clinical trial simulator to analyse the impact of three different types of variation on the outcome of a challenge study of influenza treatments for infected patients, including individual patient variability in the response to the drug, the variance of the measurement procedure, and the variance of the lower limit of quantification of endpoint measurements. In addition, we investigated the impact of protocol variation on clinical trial outcome. We found that the greatest source of variance was inter-individual variability in the natural course of infection. Running a larger phase II study can save up to $38 million, if an unlikely to succeed phase III trial is avoided. In addition, low-sensitivity viral load assays can lead to falsely negative trial outcomes., Conclusions: Due to high inter-individual variability in natural infection, the most important variable in clinical trial design for challenge studies of potential novel influenza treatments is the number of participants. 100 participants are preferable over 50. Using more sensitive viral load assays increases the probability of a positive trial outcome, but may in some circumstances lead to false positive outcomes. Clinical trial simulations are powerful tools to identify the most important sources of variance in clinical trials and thereby help improve trial design.

Mathematical models have provided important insights into acute viral dynamics within individual patients. In this paper, we study the simplest target cell-limited models to investigate the within-host dynamics of influenza A virus infection in humans. Despite the biological simplicity of the models, we show how these can be used to understand the severity of the infection and the key attributes of possible immunotherapy and antiviral drugs for the treatment of infection at different times post infection. Through an analytic approach, we derive and estimate simple summary biological quantities that can provide novel insights into the infection dynamics and the definition of clinical endpoints. We focus on nine quantities, including the area under the viral load curve, peak viral load, the time to peak viral load and the level of cell death due to infection. Using Markov chain Monte Carlo methods, we fitted the models to data collected from 12 untreated volunteers who participated in two clinical studies that tested the antiviral drugs oseltamivir and zanamivir. Based on the results, we also discuss various difficulties in deriving precise estimates of the parameters, even in the very simple models considered, when experimental data are limited to viral load measures and/or there is a limited number of viral load measurements post infection., (© 2016 The Authors.)

The electronic structure of DNA is determined by its nucleotide sequence, which is for instance exploited in molecular electronics. Here we demonstrate that also the DNA strand breakage induced by low-energy electrons (18 eV) depends on the nucleotide sequence. To determine the absolute cross sections for electron induced single strand breaks in specific 13 mer oligonucleotides we used atomic force microscopy analysis of DNA origami based DNA nanoarrays. We investigated the DNA sequences 5'-TT(XYX)3TT with X = A, G, C and Y = T, BrU 5-bromouracil and found absolute strand break cross sections between 2.66 · 10(-14) cm(2) and 7.06 · 10(-14) cm(2). The highest cross section was found for 5'-TT(ATA)3TT and 5'-TT(ABrUA)3TT, respectively. BrU is a radiosensitizer, which was discussed to be used in cancer radiation therapy. The replacement of T by BrU into the investigated DNA sequences leads to a slight increase of the absolute strand break cross sections resulting in sequence-dependent enhancement factors between 1.14 and 1.66. Nevertheless, the variation of strand break cross sections due to the specific nucleotide sequence is considerably higher. Thus, the present results suggest the development of targeted radiosensitizers for cancer radiation therapy.

We assess the pros and cons of a large panel of DFT exchange-correlation functionals for the prediction of the electronic structure of hydrogen-rich peptide radicals formed after electron attachment on a protonated peptide. Indeed, despite its importance in the understanding of the chemical changes associated with the reduction step, the question of the attachment site of an electron and, more generally, of the reduced species formed in the gas phase through electron-induced dissociation (ExD) processes in mass spectrometry is still a matter of debate. For hydrogen-rich peptide radicals in which several positive groups and low-lying π* orbitals can capture the incoming electron in ExD, inclusion of full Hartree-Fock exchange at long-range interelectronic distance is a prerequisite for an accurate description of the electronic states, thereby excluding several popular exchange-correlation functionals, e.g., B3LYP, M06-2X, or CAM-B3LYP. However, we show that this condition is not sufficient by comparing the results obtained with asymptotically correct range-separated hybrids (M11, LC-BLYP, LC-BPW91, ωB97, ωB97X, and ωB97X-D) and with reference CASSCF-MRCI and EOM-CCSD calculations. The attenuation parameter ω significantly tunes the spin density distribution and the excited states vertical energies. The investigated model structures, ranging from methylammonium to hexapeptide, allow us to obtain a description of the nature and energy of the electronic states, depending on (i) the presence of hydrogen bond(s) around the cationic site(s), (ii) the presence of π* molecular orbitals (MOs), and (iii) the selected DFT approach. It turns out that, in the present framework, LC-BLYP and ωB97 yields the most accurate results.

We present the results of a theoretical investigation focusing on the solvent structure surrounding the -1, 0 and +1 charged species of F, Cl, Br and I halogen atoms and F2, Cl2, Br2 and I2 di-halogen molecules in a methanol solvent and its influence on the electronic structure of the solute molecules. Our results show a large stabilizing effect arising from the solute-solvent interactions. Well-formed first solvation shells are observed for all species, the structure of which is strongly influenced by the charge of the solute species. Detailed analysis reveals that coordination number, CN, solvent orientation, θ, and solute-solvent distance, d, are important structural characteristics which are coupled to changes in the electronic structure of the solute. We propose that the fundamental chemistry of any solute species is generally regulated by these solvent degrees of freedom.

In view of preparing Cu polynuclear complexes with dipyrromethene ligands, the mononuclear complexes [Cu(II)(dipy)2] (dipyH = 5-phenyldipyrromethene) and [Cu(II)(dpdipy)2] (dpdipyH = 1,5,9-triphenyldipyrromethene) have been prepared and characterized by X-ray crystallography, mass spectrometry and EPR spectroscopy. Their peculiar redox and spectroscopic (absorption/emission) behaviours are discussed. In contrast to Cu(II) complexes of 1,1'-bidypyrrin, the reduction electrolysis of [Cu(II)(dpdipy)2] leads to decomposition products on a time scale of a few hours. Moreover in relation to this observation, [Cu(I)(dpdipy)2](-) could not be synthesized in spite of the Cu(I) core protection by the phenyl substituents in ortho position of the nitrogen atoms. Theoretical calculations provide some explanations for this instability. Interestingly [Cu(II)(dipy)2] and [Cu(II)(dpdipy)2] display weak luminescence at room temperature, attributed to a ligand centered emission.

We predict that electron attachment may be used with ESI-MS techniques to observe neutral Al metal aqua-oxo-hydroxo species and the complex polymerization and precipitation reactions in which they participate. Neutral aqueous metal species have, so far, been invisible to ESI-MS techniques.

Low energy electron-attachment-induced damage in DNA, where dissociation channels may involve multiple bonds including complex bond rearrangements and significant nuclear motions, is analyzed here. Quantum mechanics/molecular mechanics (QM/MM) calculations reveal how rearrangements of electron density after vertical electron attachment modulate the position and dynamics of the atomic nuclei in DNA. The nuclear motions involve the elongation of the P-O (P-O(3') and P-O(5')) and C-C (C(3')-C(4') and C(4')-C(5')) bonds for which the acquired kinetic energy becomes high enough so that the neighboring C(3')-O(3') or C(5')-O(5') phosphodiester bond may break almost immediately. Such dynamic behavior should happen on a very short time scale, within 15-30 fs, which is of the same order of magnitude as the time scale predicted for the excess electron to localize around the nucleobases. This result indicates that the C-O phosphodiester bonds can break before electron transfer from the backbone to the base.

We present results showing that our recently developed density functional theory (DFT)-based speciation model of the aqueous Al(3+) system has the potential to improve the interpretations of ESI-MS studies of aqueous metal cation hydrolytic speciation. The main advantages of our method are that (1) it allows for the calculation of the relative abundance of a given species which may be directly assigned to the signal intensity in a mass spectrum; (2) in cases where species with identical m⁄z ratios may coexist, the assignment can be unambiguously assigned based on their theoretical relative abundances. As a demonstration of its application, we study four pairs of monomer and dimer aqueous Al(3+) species, each with identical m/z ratio. For some of these pairs our method predicts that the dominant species changes from the monomer to the dimer species under varying pH conditions.

Herein, we report on the structure and dynamics of the aqueous Ca(2+) system studied by using ab initio molecular dynamics (AIMD) simulations. Our detailed study revealed the formation of well-formed hydration shells with characteristics that were significantly different to those of bulk water. To facilitate a robust comparison with state-of-the-art X-ray absorption fine structure (XAFS) data, we employ a 1st principles MD-XAFS procedure and directly compare simulated and experimental XAFS spectra. A comparison of the data for the aqueous Ca(2+) system with those of the recently reported Zn(2+), Fe(3+), and Al(3+) species showed that many of their structural characteristics correlated well with charge density on the cation. Some very important exceptions were found, which indicated a strong sensitivity of the solvent structure towards the cation's valence electronic structure. Average dipole moments for the 2nd shell of all cations were suppressed relative to bulk water., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Car-Parrinello-based molecular dynamics (CPMD) method was used to investigate the ion-pairing behavior between Cl(-) and Al(3+) ions in an aqueous AlCl(3) solution containing 63 water molecules. A series of constrained simulations was carried out at 300 K for up to 16 ps each, with the internuclear separation (r(Al-Cl)) between the Al(3+) ion and one of the Cl(-) ions held constant. The calculated potential of mean force (PMF) of the Al(3+)-Cl(-) ion pair shows a global minimum at r(Al-Cl) = 2.3 Å corresponding to a contact ion pair (CIP). Two local minima assigned to solvent-separated ion pairs (SSIPs) are identified at r(Al-Cl) = 4.4 and 6.0 Å. The positions of the free energy minima coincide with the hydration-shell intervals of the Al(3+) cation, suggesting that the Cl(-) ion is inclined to reside in regions with low concentrations of water molecules, that is, between the first and second hydration shells of Al(3+) and between the second shell and the bulk. A detailed analysis of the solvent structure around the Al(3+) and Cl(-) ions as a function of r(Al-Cl) is presented. The results are compared to structural data from X-ray measurements and unconstrained CPMD simulations of single Al(3+) and Cl(-) ions and AlCl(3) solutions. The dipole moments of the water molecules in the first and second hydration shells of Al(3+) and in the bulk region and those of Cl(-) ions were calculated as a function of r(Al-Cl). Major changes in the electronic structure of the system were found to result from the removal of Cl(-) from the first hydration shell of the Al(3+) cation. Finally, two unconstrained CPMD simulations of aqueous AlCl(3) solutions corresponding to CIP and SSIP configurations were performed (17 ps, 300 K). Only minor structural changes were observed in these systems, confirming their stability.

We investigate possible mutations in the genetic code induced by cisplatin with an approach combining molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. Specifically, the impact of platination on the natural tautomeric equilibrium in guanine-cytosine (GC) base pairs is assessed to disclose the possible role played by non-canonical forms in anti-tumour activity. To obtain valuable predictions, the main interactions present in a real DNA environment, namely hydration and stacking, are simultaneously taken into account. According to our results, the Pt-DNA adduct promotes a single proton transfer reaction in GC in the DNA sequence AG[combining low line]G[combining low line]C. Such rare tautomers might play an important role in the cisplatin biological activity since they meet the stability requirements necessary to promote a permanent mutation.

First-principles dynamics simulations (DFT, PBE96, and PBE0) and electron scattering calculations (FEFF9) provide near-quantitative agreement with new and existing XAFS measurements for a series of transition-metal ions interacting with their hydration shells via complex mechanisms (high spin, covalency, charge transfer, etc.). This analysis does not require either the development of empirical interparticle interaction potentials or structural models of hydration. However, it provides consistent parameter-free analysis and improved agreement with the higher-R scattering region (first- and second-shell structure, symmetry, dynamic disorder, and multiple scattering) for this comprehensive series of ions. DFT+GGA MD methods provide a high level of agreement. However, improvements are observed when exact exchange is included. Higher accuracy in the pseudopotential description of the atomic potential, including core polarization and reducing core radii, was necessary for very detailed agreement. The first-principles nature of this approach supports its application to more complex systems.

Low-energy electrons (LEEs) play an important role in nanolithography, atmospheric chemistry, and DNA radiation damage. Previously, the cleavage of specific chemical bonds triggered by LEEs has been demonstrated in a variety of small organic molecules such as halogenated benzenes and DNA nucleobases. Here we present a strategy that allows for the first time to visualize the electron-induced dissociation of single chemical bonds within complex, but well-defined self-assembled DNA nanostructures. We employ atomic force microscopy to image and quantify LEE-induced bond dissociations within specifically designed oligonucleotide targets that are attached to DNA origami templates. In this way, we use a highly selective approach to compare the efficiency of the electron-induced dissociation of a single disulfide bond with the more complex cleavage of the DNA backbone within a TT dinucleotide sequence. This novel technique enables the fast and parallel determination of DNA strand break yields with unprecedented control over the DNA's primary and secondary structure. Thus the detailed investigation of DNA radiation damage in its most natural environment, e.g., DNA nucleosomes constituting the chromatin, now becomes feasible.

The hypothetical protection of genes from oxidative damage provided by the G-rich telomeric overhangs located at the end of chromosomes, which consist, in humans, of single strands of TTAGGG sequence repeats, is investigated here. First principle Moller-Plesset perturbation theory calculations reveal that the TTAGGG human telomere sequence is particularly prone to oxidation and can act as a profound hole trap as deep as a sequence of five consecutive guanines. In addition, we show that the sequence dependence is very important and that modifications in the human telomeric sequence can induce crucial changes in the electronic structure of the sequence, with concomitant increase of the ionization energy. These theoretical results provide, for the first time, quantitative data indicating a high and unique efficiency of the human telomeric sequence as a trap in long-range hole migration which will aid in the design of subsequent experiments.

Electron holes are known to migrate along the DNA or RNA duplexes and to localize preferentially on successive guanines. The stationary point conformations of Gua pairs that can trap or let pass these holes have been characterized by quantum chemistry calculations. Here we show their recurrent occurrence in DNA and RNA X-ray structures, often in quadruplex conformations or in interaction with proteins, ligands or metal ions. These findings give support to the biological, possibly regulatory, roles of charge migration in cell functioning.

The unprotonated and protonated monoreduced forms of the polyazaaromatic Ru(II) coordination complexes [Ru(tap)(3)](2+) and [Ru(tap)(2)(phen)](2+) (tap = 1,4,5,8-tetraazaphenanthrene ; phen = 1,10-phenanthroline), that is, [Ru(tap)(3)](*+), [Ru(tap)(2)(phen)](*+), [Ru(tap)(2)(tap-H)](*2+), and [Ru(tap)(tap-H)(phen)](*2+), were studied by Density Functional Theory (DFT). The electron spin density of these radical cations, the isotropic Fermi-contact, and the anisotropic dipolar contributions to the hyperfine coupling constants of the H nuclei were calculated in vacuo and using a continuum model for water solvation. For [Ru(tap)(2)(phen)](*+), as well as for its protonated form, the DFT results show that the unpaired electron is not localized on the phen ligand. For both [Ru(tap)(3)](*+) and [Ru(tap)(2)(phen)](*+), they reveal high electron spin density in the vicinity of tap H-2 and tap H-7 (the H atoms in the ortho position of the tap non-chelating N atoms). These results are in full agreement with recent steady-state (1)H photo-Chemically Induced Dynamic Nuclear Polarization (photo-CIDNP) measurements. The DFT calculations performed for the protonated species also predict major (1)H photo-CIDNP enhancements at these positions. Interestingly, they indicate significantly different polarization for tap H-9,10, suggesting that the occurrence of a photoinduced electron transfer with protonation of the reduced species might be detected by high-precision photo-CIDNP experiments.

Results of ab initio molecular dynamics (AIMD) simulations (density functional theory+PBE96) of the dynamics of waters in the hydration shells surrounding the Zn(2+) ion (T approximately 300 K, rho approximately 1 gm/cm(3)) are compared to simulations using a combined quantum and classical molecular dynamics [AIMD/molecular mechanical (MM)] approach. Both classes of simulations were performed with 64 solvating water molecules ( approximately 15 ps) and used the same methods in the electronic structure calculation (plane-wave basis set, time steps, effective mass, etc.). In the AIMD/MM calculation, only six waters of hydration were included in the quantum mechanical (QM) region. The remaining 58 waters were treated with a published flexible water-water interaction potential. No reparametrization of the water-water potential was attempted. Additional AIMD/MM simulations were performed with 256 water molecules. The hydration structures predicted from the AIMD and AIMD/MM simulations are found to agree in detail with each other and with the structural results from x-ray data despite the very limited QM region in the AIMD/MM simulation. To further evaluate the agreement of these parameter-free simulations, predicted extended x-ray absorption fine structure (EXAFS) spectra were compared directly to the recently obtained EXAFS data and they agree in remarkable detail with the experimental observations. The first hydration shell contains six water molecules in a highly symmetric octahedral structure is (maximally located at 2.13-2.15 A versus 2.072 A EXAFS experiment). The widths of the peak of the simulated EXAFS spectra agree well with the data (8.4 A(2) versus 8.9 A(2) in experiment). Analysis of the H-bond structure of the hydration region shows that the second hydration shell is trigonally bound to the first shell water with a high degree of agreement between the AIMD and AIMD/MM calculations. Beyond the second shell, the bonding pattern returns to the tetrahedral structure of bulk water. The AIMD/MM results emphasize the importance of a quantum description of the first hydration shell to correctly describe the hydration region. In these calculations the full d(10) electronic structure of the valence shell of the Zn(2+) ion is retained. The simulations show substantial and complex charge relocation on both the Zn(2+) ion and the first hydration shell. The dipole moment of the waters in the first hydration shell is 3.4 D (3.3 D AIMD/MM) versus 2.73 D bulk. Little polarization is found for the waters in the second hydration shell (2.8 D). No exchanges were seen between the first and the second hydrations shells; however, many water transfers between the second hydration shell and the bulk were observed. For 64 waters, the AIMD and AIMD/MM simulations give nearly identical results for exchange dynamics. However, in the larger particle simulations (256 waters) there is a significant reduction in the second shell to bulk exchanges.

Vertical ionization potentials (IPs) of nucleobases embedded in a fully solvated DNA fragment (12-mer B-DNA fragment + 22 sodium counterions + 5760 water molecules equilibrated to 298 K) have been calculated using a combined quantum mechanical molecular mechanics (QM/MM) approach. Calculations of the vertical IP of the anion Cl(-) are reported that support the accuracy of the application of a QM/MM method to this problem. It is shown that the pi nucleotide HOMO origin for the emitted electron is localized on the base by the hydration structure surrounding the DNA in a way similar to that recently observed for pyrimidine nucleotides in aqueous solutions (Slavicek, P.; et al. J. Am. Chem. Soc. 2009, 131, 6460). In a first step, a high level of theory, CCSD(T)/aug-cc-pVDZ, was used to calculate the vertical IP of each of the four single bases isolated in the QM region while the remaining DNA fragment, counterions, and water solvent molecules were included in the MM region. The calculated vertical IPs show a large positive shift of 3.2-3.3 eV compared to the corresponding gas-phase values. This shift is similar for all four DNA bases. The origin of the large increase in vertical IPs of nucleobases is found to be the long-range electrostatic interactions with the solvation structure outside the DNA helix. Thermal fluctuations in the fluid can result in IP changes of roughly 1 eV on a picosecond time scale. IPs of pi-stacked and H-bonded clusters of DNA bases were also calculated using the same QM/MM model but with a lower level of theory, B3LYP/6-31G(d=0.2). An IP shift of 4.02 eV relative to the gas phase is found for a four-base-pair B-DNA duplex configuration. The primary goal of this work was to estimate the influence of long-range solvation interactions on the ionization properties of DNA bases rather than provide highly precise IP evaluations. The QM/MM model presented in this work provides an attractive method to treat the difficult problem of incorporating a detailed long-range structural model of physiological conditions into investigations of the electronic processes in DNA.

The charge transfer process in an ionized stacking of two consecutive guanines (G(5')G(3'))(+) has been studied by means of state-averaged CASSCF/MRCI and RASSCF/RASPT2 calculations. The ground and two first excited states of the radical cation have been characterized, and the topology of the corresponding potential energy surfaces (PESs) has been studied as a function of all intermolecular geometrical parameters. The results demonstrate that the charge transfer process in (G(5')G(3'))(+) is governed by the avoiding crossing between the ground and first excited states of the complex. Relative translation motions of both guanines in their molecular planes are shown to lead to the charge migration between G(5') and G(3'). Five stationary points (three minima and two saddle points) have been characterized along the reaction path describing the passage of the positive charge from G(5') to G(3'). The global minimum on the PES is found to correspond to the charge configuration G(5')(+)G(3'). The existence of an intermediate minimum along the reaction path has been established, characterizing a structure where the positive charge is equally distributed between the two guanines. The calculated energy profile allowed us to determine the height of the potential energy barrier (7.33 kcal/mol) and to evaluate the electronic coupling at a geometry close to the avoiding crossing (3.6 kcal/mol). Test calculations showed that the topology of the ground state PES of the complex GG(+) is qualitatively conserved upon optimization of the intramolecular geometrical parameters of the stationary points.

The ionization of the four DNA bases is investigated by means of ab initio calculations. Accurate values of the gas-phase vertical and adiabatic ionization potentials (IP) are obtained at the MP2/6-31G(2d(0.8,alpha(d)),p) level of theory. The need of introducing extra polarization to the standard 6-31G(d,p) basis set is demonstrated by test calculations and an optimal value of alpha(d) = 0.1 is obtained. Ionization to electronically excited radical cations is also considered. The low-lying excited states of the cations are characterized for the first time. The topology of the corresponding potential energy surfaces is qualitatively described in terms of the stationary points (minima and saddle points) located on these surfaces. A conical intersection is characterized for the first time on the ground-state potential energy surface of all cations. It arises from the crossing of the adiabatic surfaces of the ground and first excited state at planar geometries. A nonplanar minimum is observed for the cytosine cation only. The geometry and electronic changes occurring along these surfaces are analyzed, leading to a comparison between the different nucleobase cations. The study of larger ionized systems related to DNA is rendered possible thanks to the optimized medium size basis set proposed in this work, as exemplified by the calculation of the IP of a stacked dimer of guanines.

His-aromatic complexes, with the His located above the aromatic plane, are stabilized by π-π, δ(+)-π and/or cation-π interactions according to whether the His is neutral or protonated and the partners are in stacked or T-shape conformations. Here we attempt to probe the relative strength of these interactions as a function of the geometry and protonation state, in gas phase, in water and protein-like environments (acetone, THF and CCl4), by means of quantum chemistry calculations performed up to second order of the Møller-Plesset pertubation theory. Two sets of conformations are considered for that purpose. The first set contains 89 interactions between His and Phe, Tyr, Trp, or Ade, observed in X-ray structures of proteins and protein-ligand complexes. The second set contains model structures obtained by moving an imidazolium/imidazole moiety above a benzene ring or an adenine moiety. We found that the protonated complexes are much more stable than the neutral ones in gas phase. This higher stability is due to the electrostatic contributions, the electron correlation contributions being equally important in the two forms. Thus, π-π and δ(+)-π interactions present essentially favorable electron correlation energy terms, whereas cation-π interactions feature in addition favorable electrostatic energies. The protonated complexes remain more stable than the neutral ones in protein-like environments, but the difference is drastically reduced. Furthermore, the T-shape conformation is undoubtedly more favorable than the stacked one in gas phase. This advantage decreases in the solvents, and the stacked conformation becomes even slightly more favorable in water. The frequent occurrence of His-aromatic interactions in catalytic sites, at protein-DNA or protein-ligand interfaces and in 3D domain swapping proteins emphasize their importance in biological processes.