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In this article, we investigate the mechanisms of DNA ionization upon irradiation by 0.5 meV alpha particles. We focus on the sugar-phosphate group and its hydration shell. In radiation chemistry, the term quasi-direct effect refers the physical and chemical responses taking place after irradiation of solvent molecules pertaining to the solvation shells of solutes. The molecular mechanisms accounting for the quasi-direct effect are actually largely elusive, especially for those prevailing in the early timescales (< 10–12 s). We report Real-Time Time-Dependent Auxiliary Density Functional Theory simulations carried out within the framework of hybrid QM/MM scheme (Quantum Mechanics/Molecular Mechanics) with polarizable and non-polarizable embedding. Ten water molecules from the solvation shell of DNA backbone are independently irradiated. We find that during the first femtoseconds after irradiation, the holes formed on the irradiated water remain at their sites of formation. Electrostatic induction within the environment does not significantly impact charge migrations. We address the hypothesis that charge migration driven by electron correlation is responsible for an ultrafast H2O+ to DNA charge transfers, which would account for a quasi-direct effect. We find that pure charge migration at fixed nuclear positions is not responsible for the quasi-direct effect when considering sugar-phosphate solvation shells.

We recently adapted the Auxiliary DFT framework as implemented in deMon2k to the simulation of time-dependent problems via the Runge and Gross equations. Our implementation of the so-called Real-Time-Time-Dependent ADFT (RT-TD-ADFT) fully benefits from the algorithms available in deMon2k to carry out variational density fitting, notably the MINRES algorithm recently proposed for self-consistent-field calculations. We test here MINRES for the first time in the context of RT-TD-ADFT. We report extensive benchmarks calculations to assess the reliability of the ADFT framework. These encompass the construction of absorption spectra in the gas phase and in solvent, the calculation of electronic stopping power curves, the irradiation of zeolites by swift ions and the investigation of charge migrations with attosecond time resolution. All our results are very encouraging. We show that even small auxiliary basis sets are sufficient to obtain results almost undisguisable from those obtained with large and flexible auxiliary bases. Overall, we establish the reliability of RT-TD-ADFT to simulate electronics dynamics in large or very large molecular systems.

deMon2k is a readily available program specialized in Density Functional Theory (DFT) simulations within the framework of Auxiliary DFT. This article is intended as a tutorial-review of the capabilities of the program for molecular simulations involving ground and excited electronic states. The program implements an additive QM/MM (quantum mechanics/molecular mechanics) module relying either on non-polarizable or polarizable force fields. QM/MM methodologies available in deMon2k include ground-state geometry optimizations, ground-state Born–Oppenheimer molecular dynamics simulations, Ehrenfest non-adiabatic molecular dynamics simulations, and attosecond electron dynamics. In addition several electric and magnetic properties can be computed with QM/MM. We review the framework implemented in the program, including the most recently implemented options (link atoms, implicit continuum for remote environments, metadynamics, etc.), together with six applicative examples. The applications involve (i) a reactivity study of a cyclic organic molecule in water; (ii) the establishment of free-energy profiles for nucleophilic-substitution reactions by the umbrella sampling method; (iii) the construction of two-dimensional free energy maps by metadynamics simulations; (iv) the simulation of UV-visible absorption spectra of a solvated chromophore molecule; (v) the simulation of a free energy profile for an electron transfer reaction within Marcus theory; and (vi) the simulation of fragmentation of a peptide after collision with a high-energy proton.

Population analyses are part of the theoretical chemist’s toolbox. They provide means to extract information about the repartition of the electronic density among molecules or solids. The values of atomic multipoles in a molecule can shed light on its electrostatic properties and may help to predict how different molecules could interact or to rationalize chemical reactivity for instance. Not being physical observables to which a quantum mechanical operator can be associated, atomic charges and higher order atomic multipoles cannot be defined unambiguously in a molecule, and therefore, several population schemes (PS) have been devised in the last decades. In the context of density functional theory (DFT), PS based on the electron density seem to be best grounded. In particular, some groups have proposed various iterative schemes the outcomes of which are very encouraging. Modern implementations of DFT that are for example based on density fitting techniques permit the investigation of molecular systems comprising of hundreds of atoms. However, population analyses following iterative schemes may become very CPU time consuming for such large systems. In this article, we investigate if the computationally less expensive analyses of the variationally fitted electronic densities can be safely carried out instead of the Kohn-Sham density. It is shown that as long as flexible auxiliary function sets including f and g functions are used, the multipoles extracted from the fitted densities are extremely close to those obtained from the KS density. We further assess if the multipoles obtained through the Hirshfeld’s approach, in its standard or iterative form, can be a useful approach to calculate interaction energies in non-covalent complexes. Relative energies computed with the AMOEBA polarizable forced field combined to iterative Hirshfeld multipoles are encouraging.

Abstract When a molecular system is subjected to an external electric perturbation, originating from an electromagnetic wave or from a charged moving particle (in molecule-ion collisions), the electrons are the first particles to respond, on the attosecond timescale. Electron dynamics (ED) can be simulated by so-called real-time time-dependent density functional theory (RT-TDDFT). Within this framework, ED is driven by the electrostatic potential and by exchange-correlation potentials that fluctuate on the attosecond time scale. In vacuum the speed of light approaches 3 Å as−1. Therefore, when simulating ED in extended molecular systems the question of retardation in the propagation of the potentials has to be posed. In this contribution we investigate two types of retardation; the first one deals with retardation in the potential created by a collision with a charged projectile. This is done through the Liénard-Wiechert potential (LWP). The second one deals with retardation in the electrostatic interaction between the time-dependent electron density and its environment, here in the context of hybrid schemes coupling RT-TDDFT to polarizable Molecular Mechanics force fields (MMpol). We found that the latter retardation effects can be safely neglected because of the rapid damping vs. distance of the electric fields created by electrostatic dipole moments. This conclusion is also relevant for methodologies, coupling RT-TDDFT to implicit polarizable continuum models. On the other hand, our results recommend the use of the LWP for modelling molecule-ion collisions by first-principles simulations. Remarkably, ionization takes place on faster time scales when relativistic corrections are introduced even for incident kinetic energies of 0.1 MeV. Graphical abstract

Cellular energy production depends on electron transfer (ET) between proteins. In this theoretical study, we investigate the impact of structural and conformational variations on the electronic coupling between the redox proteins methylamine dehydrogenase and amicyanin from Paracoccus denitrificans. We used molecular dynamics simulations to generate configurations over a duration of 40 ns (sampled at 100-fs intervals) in conjunction with an ET pathway analysis to estimate the ET coupling strength of each configuration. In the wild-type complex, we find that the most frequently occurring molecular configurations afford superior electronic coupling due to the consistent presence of a water molecule hydrogen-bonded between the donor and acceptor sites. We attribute the persistence of this water bridge to a \"molecular break-water\" composed of several hydrophobic residues surrounding the acceptor site. The breakwater supports the function of nearby solvent-organizing residues by limiting the exchange of water molecules between the sterically constrained ET region and the more turbulent surrounding bulk. When the breakwater is affected by a mutation, bulk solvent molecules disrupt the water bridge, resulting in reduced electronic coupling that is consistent with recent experimental findings. Our analysis suggests that, in addition to enabling the association and docking of the proteins, surface residues stabilize and control interprotein solvent dynamics in a concerted way.

A multipoint recognition system based on a calix[6]arene is described. The calixarene core is decorated on alternating aromatic subunits by 3 imidazole arms at the small rim and 3 aniline groups at the large rim. This substitution pattern projects the aniline nitrogens toward each other when Zn(II) binds at the Tris-imidazole site or when a proton binds at an aniline. The XRD structure of the monoprotonated complex having an acetonitrile molecule bound to Zn(II) in the cavity revealed a constrained geometry at the metal center reminiscent of an entatic state. Computer modeling suggests that the aniline groups behave as a tritopic monobasic site in which only 1 aniline unit is protonated and interacts with the other 2 through strong hydrogen bonding. The metal complex selectively binds a monoprotonated diamine vs. a monoamine through multipoint recognition: coordination to the metal ion at the small rim, hydrogen bonding to the calix-oxygen core, CH/π interaction within the cavity's aromatic walls, and H-bonding to the anilines at the large rim.

We have studied electron transfers (ET) between electron donors and acceptors, taking as illustrative example the case of ET in methionine enkephalin. Recent pulse and gamma radiolysis experiments suggested that an ultrafast ET takes place from the C-terminal tyrosine residue to the N-terminal, oxidized, methionine residue. According to standard theoretical frameworks like the Marcus theory, ET can be decomposed into two successive steps: i) the achievement through thermal fluctuations, of a set of nuclear coordinates associated with degeneracy of the two electronic states, ii) the electron tunneling from the donor molecular orbital to the acceptor molecular orbital. Here, we focus on the analysis of the time-dependent electronic dynamics during the tunneling event. This is done by extending the approaches based on the topological analyses of stationary electronic density and of the electron localization function (ELF) to the time-dependent domain. Furthermore, we analyzed isosurfaces of the divergence of the current density, showing the paths that are followed by the tunneling electron from the donor to the acceptor. We show how these functions can be calculated with constrained density functional theory. Beyond this work, the topological tools used here can open up new opportunities for the electronic description in the time-dependent domain.

We summarize in this article the recent progress made in our laboratories in the development of numerical approaches dedicated to investigating ultrafast physicochemical responses of biological matter subjected to ionizing radiations. Our modules are integrated into the deMon2k software which is a readily available program with highly optimized algorithms for conducting Auxiliary Density Functional Theory (ADFT) calculations. We have developed a computational framework based on Real-Time Time-dependent ADFT to simulate the electronic responses of molecular systems to strong perturbations, while molecular dynamics simulations in the ground and excited states (Ehrenfest dynamics) are available to simulate irradiation-induced ultrafast bond breaking/formation. Constrained ADFT and Multi-component ADFT have also been incorporated to simulate charge transfer processes and nuclear quantum effects, respectively. Finally, a coupling to polarizable force fields further permits to realistically account for the electrostatic effects that the systems’ environment has on the perturbed electron density. The code runs on CPU or hybrid CPU/GPU architectures affording simulations of systems comprised up to 1000 atoms at the DFT level with controlled numerical accuracy. We illustrate the applications of these methodologies by taking results from our recent articles that aimed principally at understanding experimental data from pulse radiolysis experiments.

RNA polymerases are molecular machines of great fidelity, which can recognize matched NTPs from unmatched NTPs and 2′-dNTPs. We investigated by a stochastic simulation algorithm the whole nucleotide addition cycle based on an event-driven model. This model allows us to examine possible molecular origins of the high fidelity of RNA polymerases. For unmatched NTP selectivity, the conclusions drawn from simulated elongation rates corroborate those derived from structural analysis. The presence of two conformations (Esite and pre-insertion site) for the incoming nucleotide before the polymerization reaction is sufficient to allow selectivity. Concerning sugar selectivity, our results indicate that selectivity is only achievable if slow chemical reactions occur for 2′-dNTP. These results can be used to understand recent experimental observations.