Influence of Solvents and Halogenation on ESIPT of Benzimidazole Derivatives for Designing Turn-on Fluorescence Probes.

This work reports a theoretical investigation of the solvent polarity as well as the halogenation of benzimidazole derivatives during excited state intramolecular proton transfer (ESIPT). It details how the environment and halogen substitution may contribute to the efficiency of ESIPT upon keto-enol tautomerism and exploits this effect to design fluorescence sensing. For this purpose, we first examine the conformational equilibrium of benzimidazole derivatives containing different halogen atoms, which results in intramolecular proton transfer, using density-functional theory (DFT) combined with the polarizable continuum model (PCM). Then we evaluate the fluorescence of the benzimidazole derivatives in different dielectric constants within time-dependent DFT (TD-DFT) approaches. Our results quantitatively allow the determination of large Stokes shifts in nonpolar solvents around 100 nm. These theoretical results are in agreement with experimental solvatochromism studies of benzimidazoles. The effect of halogenation, with fluorine, chlorine, and bromine, is less important than solvent polarization when ESIPT takes place. Thus, halogenation can be properly chosen depending on the interest of the synthesis of benzimidazole-based turn-on fluorescence in appropriate solvents.

Role of the Solvent and Intramolecular Hydrogen Bonds in the Antioxidative Mechanism of Prenylisoflavone from Leaves of Vatairea guianensis.

This work discusses the electron structure, antioxidative properties, and solvent contribution of two new antioxidant molecules discovered, named S10 and S11, extracted from a medicinal plant called Vatairea guianensis, found in the Amazon rain-forest. To gain a better understanding, a study using density functional theory coupled with the polarizable-continuum model and the standard 6-311++G(d,p) basis set was conducted. The results indicate that S10 has a higher antioxidant potential than S11, confirming the experimental expectations. In the gas phase, the hydrogen atom transfer route dominates the hydrogen scavenging procedure. However, in the water solvents, the antioxidant mechanism prefers the sequential proton loss electron transfer mechanism. Furthermore, the solvent plays a fundamental role in the antioxidant mechanism. The formation of an intramolecular OH···OCH3 hydrogen bond is crucial for accurately describing the hydrogen scavenging phenomenon, better aligning with the experimental data. The results suggest that the two isoflavones investigated are promising for the pharmacologic and food industries.

Calculation of the one- and two-photon absorption spectra of water-soluble stilbene derivatives using a multiscale QM/MM approach.

We calculated the one- (OPA) and two-photon absorption (TPA) spectra of two large water-soluble stilbene derivatives presenting TPA cross sections of about 400 GM. However, the reported experimental TPA spectra present a spectral gap region, and a theoretical study of these promising molecules seems now timely and relevant. These molecules are composed of 200 or more atoms, becoming a challenge to obtain the TPA spectra even using density functional theory at the time-dependent quadratic response formalism. Thus, both OPA and TPA were also calculated using the INDO-S semi-empirical method. We used explicit solvent molecules using the sequential-quantum mechanics/molecular mechanics to include the solvent effects. Our results show that different transitions are participating in the OPA and TPA processes and that exchange-correlation functionals, including larger Hartree-Fock contributions, provide a better description of the OPA spectra; however, the opposite trend is observed on the TPA spectra. Alternatively, INDO-S/CISD, including contributions from single and double excitations, systematically describes both OPA and TPA bands with similar shifts and better reproduces the relative intensities of the two TPA bands compared to the experimental ones. The OPA spectra are characterized by a Highest Occupied Molecular Orbital-Lowest Unoccupied Molecular Orbital (HOMO-LUMO) excitation, while the low-energy TPA band is ascribed to a single transition encompassing the (HOMO-1)-LUMO and HOMO-(LUMO+1) excitations and the high-energy one is a combination of several transitions. Thus, although more studies are required to better assess the capability of the INDO-S/CISD method in describing the TPA spectra of large molecules, our results corroborate that it is a promising alternative.

The Solute Polarization and Structural Effects on the Nonlinear Optical Response of Based Chromone Molecules.

The solute polarization due to solvent is a an electrostatic quantum effect that impacts diverse molecular properties, including the nonlinear optical response of a material. An iterative procedure that allows updating the solute charge distribution in the presence of the solvent is combined with a sequential Monte Carlo/Quantum Mechanics methodology and Density Functional Theory methods to evaluate the nonlinear optical (NLO) response using the hyper Rayleigh scattering (HRS) of a series of chromones recently identified in Chamaecrista diphylla, an herbaceous plant abundant throughout the Americas and used in folk medicine. From this study, it is determined that from gas to solvent environment, the systems acquire low refractive index (n) and an improvement of the first hyperpolarizability (ßHRS ), signaling potential NLO uses. It is shown that the octupolar contributions (ßJ=3 ) superate the dipolar ones (ßJ=1 ) and dominate the second-order optical response in both gas and liquid phases, which indicate nontrivial optical materials. Moreover, the solvent environment and structural changes in the periphery can tune significantly the dipolar/octupolar balance, showing a key to control the decoupling between these contributions.

Ultrafast Intersystem Crossing Dynamics of 6-Selenoguanine in Water.

Rationalizing the photochemistry of nucleobases where an oxygen is replaced by a heavier atom is essential for applications that exploit near-unity triplet quantum yields. Herein, we report on the ultrafast excited-state deactivation mechanism of 6-selenoguanine (6SeGua) in water by combining nonadiabatic trajectory surface-hopping dynamics with an electrostatic embedding quantum mechanics/molecular mechanics (QM/MM) scheme. We find that the predominant relaxation mechanism after irradiation starts on the bright singlet S2 state that converts internally to the dark S1 state, from which the population is transferred to the triplet T2 state via intersystem crossing and finally to the lowest T1 state. This S2 → S1 → T2 → T1 deactivation pathway is similar to that observed for the lighter 6-thioguanine (6tGua) analogue, but counterintuitively, the T1 lifetime of the heavier 6SeGua is shorter than that of 6tGua. This fact is explained by the smaller activation barrier to reach the T1/S0 crossing point and the larger spin-orbit couplings of 6SeGua compared to 6tGua. From the dynamical simulations, we also calculate transient absorption spectra (TAS), which provide two time constants (τ1 = 131 fs and τ2 = 191 fs) that are in excellent agreement with the experimentally reported value (τexp = 130 ± 50 fs) (Farrel et al. J. Am. Chem. Soc. 2018, 140, 11214). Intersystem crossing itself is calculated to occur with a time scale of 452 ± 38 fs, highlighting that the TAS is the result of a complex average of signals coming from different nonradiative processes and not intersystem crossing alone.

Free-Energy Landscape of the SN2 Reaction CH3Br + Cl- → CH3Cl + Br- in Different Liquid Environments.

This work describes in detail the reaction path of the well-known SN2 reaction CH3Br + Cl- → CH3Cl + Br-, whose reaction rate has a huge variation with the solvent in the gas phase and in protic and aprotic liquid environments. We employed the ASEC-FEG method to optimize for minima (reactants and products) and saddle points (transition states) in the in-solution free-energy hypersurface. The method takes atomistic details of the solvent into account. A polarizable continuum model (PCM) has also been employed for comparison. The most perceptive structural changes are noted in aqueous solution by using the ASEC-FEG approach. The activation energies in all solvents, estimated by means of free-energy perturbation calculations, are in good agreement with the experimental data. The total solute-solvent hydrogen bonds play an important role in the increased barrier height observed in water and are therefore crucial to explain the huge decrease in the kinetic constant. It is also found that the hydration shell around the ions breaks itself spontaneously to accommodate the molecule, thus forming minimum energy complexes.

Preferential solvation and optical properties of eumelanin building blocks in binary mixture of methanol and water.

Employing a sequential quantum mechanical/molecular mechanical approach for polar protic solvents, we study the absorption spectrum of eumelanin building blocks including monomers, dimers, and tetramers in pure water and methanol and three water-methanol binary mixtures having water molar fractions (Xw = 0.25, 0.50, and 0.75). The binary mixture of solvents is a common situation in experiments, but theoretical studies are limited to the use of continuum models. Here, we use explicit solvent molecules, and specific solute-solvent interaction is analyzed and seen to play an important role. Effects of the electronic polarization of solute by the environment were included using a reliable iterative scheme. The results illustrate that the monomers, dimers, and tetramers are preferably solvated by methanol, but the composition of the mixture in the vicinity of the solute molecules is different from the bulk composition with a preferential microsolvation (hydrogen bonds) in water for most species considered. It is observed that the short-range electrostatic polarization effects of the hydrogen bonds lead to a slight blue shift of the excitation energies when the concentration of water in the mixture is enhanced. For the same species, there is an enhancement of the higher-energy absorption intensity caused by long-range electrostatic interactions with the environment and that the behavior of the experimental spectrum, which is characterized by a nearly monotonic decay from the ultraviolet to the infrared, is qualitatively reproduced by the superposition of the absorption spectra of monomers, dimers, and tetramers in the liquid phase.

Free Energy Computation for an Isomerizing Chromophore in a Molecular Cavity via the Average Solvent Electrostatic Configuration Model: Applications in Rhodopsin and Rhodopsin-Mimicking Systems.

We present a novel technique for computing the free energy differences between two chromophore "isomers" hosted in a molecular environment (a generalized solvent). Such an environment may range from a relatively rigid protein cavity to a flexible solvent environment. The technique is characterized by the application of the previously reported "average electrostatic solvent configuration" method, and it is based on the idea of using the free energy perturbation theory along with a chromophore annihilation procedure in thermodynamic cycle calculations. The method is benchmarked by computing the ground-state room-temperature relative stabilities between (i) the cis and trans isomers of prototypal animal and microbial rhodopsins and (ii) the analogue isomers of a rhodopsin-like light-driven molecular switch in methanol. Furthermore, we show that the same technology can be used to estimate the activation free energy for the thermal isomerization of systems i-ii by replacing one isomer with a transition state. The results show that the computed relative stability and isomerization barrier magnitudes for the selected systems are in line with the available experimental observation in spite of their widely diverse complexity.

On the population of triplet states of 2-seleno-thymine.

The population and depopulation mechanisms leading to the lowest-lying triplet states of 2-Se-Thymine were studied at the MS-CASPT2/cc-pVDZ level of theory. Several critical points on different potential energy hypersurfaces were optimized, including minima, conical intersections, and singlet-triplet crossings. The accessibility of all relevant regions on the potential energy hypersurfaces was investigated by means of minimum energy paths and linear interpolation in internal coordinates techniques. Our analysis indicates that, after the population of the bright S2 state in the Franck-Condon region, the first photochemical event is a barrierless evolution towards one of its two minima. After that, three viable photophysical deactivation paths can take place. In one of them, the population in the S2 state is transferred to the T2 state via intersystem crossing and subsequently to the T1 state by internal conversion. Alternatively, the S1 state could be accessed by internal conversion through two distinct conical intersections with S2 state followed by singlet-triplet crossing with the T2 state. The absence of a second minimum on the T1 state and a small energy barrier on pathway along the potential energy surface towards the ground state from the lowest triplet state are attributed as potential reasons to explain why the lifetime of the triplet state of 2-Se-Thymine might be reduced in comparison with its thio-analogue.

Excited-State Properties and Relaxation Pathways of Selenium-Substituted Guanine Nucleobase in Aqueous Solution and DNA Duplex.

The excited-state properties and relaxation mechanisms after light irradiation of 6-selenoguanine (6SeG) in water and in DNA have been investigated using a quantum mechanics/molecular mechanics (QM/MM) approach with the multistate complete active space second-order perturbation theory (MS-CASPT2) method. In both environments, the S1 1(nSeπ5*) and S2 1(πSeπ5*) states are predicted to be the spectroscopically dark and bright states, respectively. Two triplet states, T1 3(πSeπ5*) and T2 3(nSeπ5*), are found energetically below the S2 state. Extending the QM region to include the 6SeG-Cyt base pair slightly stabilizes the S2 state and destabilizes the S1, due to hydrogen-bonding interactions, but it does not affect the order of the states. The optimized minima, conical intersections, and singlet-triplet crossings are very similar in water and in DNA, so that the same general mechanism is found. Additionally, for each excited state geometry optimization in DNA, three kind of structures ("up", "down", and "central") are optimized which differ from each other by the orientation of the C═Se group with respect to the surrounding guanine and thymine nucleobases. After irradiation to the S2 state, 6SeG evolves to the S2 minimum, near to a S2/S1 conical intersection that allows for internal conversion to the S1 state. Linear interpolation in internal coordinates indicate that the "central" orientation is less favorable since extra energy is needed to surmount the high barrier in order to reach the S2/S1 conical intersection. From the S1 state, 6SeG can further decay to the T1 3(πSeπ5*) state via intersystem crossing, where it will be trapped due to the existence of a sizable energy barrier between the T1 minimum and the T1/S0 crossing point. Although this general S2 → T1 mechanism takes place in both media, the presence of DNA induces a steeper S2 potential energy surface, that it is expected to accelerate the S2 → S1 internal conversion.

A QM/MM study of the conformation stability and electronic structure of the photochromic switches derivatives of DHA/VHF in acetonitrile solution.

We present a detailed theoretical study of the electronic absorption spectra and thermochemistry of molecular photoswitches composed of one and two photochromic units of dihydroazulene (DHA)/vinylheptafulvene (VHF) molecules. Six different isomers are considered depending on the ring opening/closure forms of the DHA units. The solvent effect of acetonitrile is investigated using a sequential Molecular Mechanics/Quantum Mechanics approach. The thermochemical investigations of these photochromic molecules were performed using the Free Energy Perturbation method, and the simulations were performed using Configurational Bias Monte Carlo. We show that to open the 5-member ring of the DHA, there is no significant gain in thermal release of energy for the back reaction when a unit or two DHA units are considered. Overall, we found agreement between the solvation free energy based on Monte Carlo simulations and the continuum solvent model. However, the cavitation term in the continuum model is shown to be a source of disagreement when the non-electrostatic terms are compared. The electronic absorption spectra are calculated using TDDFT CAM-B3LYP/cc-pVDZ. Agreement with experiment is obtained within 0.1 eV, considering statistically uncorrelated configurations from the simulations. Inhomogeneous broadening is also considered and found to be well described in all cases.

A new interpretation of the absorption and the dual fluorescence of Prodan in solution.

Remarkable interest is associated with the interpretation of the Prodan fluorescent spectrum. A sequential hybrid Quantum Mechanics/Molecular Mechanics method was used to establish that the fluorescent emission occurs from two different excited states, resulting in a broad asymmetric emission spectrum. The absorption spectra in several solvents were measured and calculated using different theoretical models presenting excellent agreement. All theoretical models [semiempirical, time dependent density functional theory and and second-order multiconfigurational perturbation theory] agree that the first observed band at the absorption spectrum in solution is composed of three electronic excitations very close in energy. Then, the electronic excitation around 340 nm-360 nm may populate the first three excited states (π-π*Lb, n-π*, and π-π*La). The ground state S0 and the first three excited states were analyzed using multi-configurational calculations. The corresponding equilibrium geometries are all planar in vacuum. Considering the solvent effects in the electronic structure of the solute and in the solvent relaxation around the solute, it was identified that these three excited states can change the relative order depending on the solvent polarity, and following the minimum path energy, internal conversions may occur. A consistent explanation of the experimental data is obtained with the conclusive interpretation that the two bands observed in the fluorescent spectrum of Prodan, in several solvents, are due to the emission from two independent states. Our results indicate that these are the n-π* S2 state with a small dipole moment at a lower emission energy and the π-π*Lb S1 state with large dipole moment at a higher emission energy.

Solvation Structures and Deactivation Pathways of Luminescent Isothiazole-Derived Nucleobases: tzA, tzG, and tzI.

The photophysical relaxation pathways of tzA, tzG, and tzI luminescent nucleobases were investigated with the MS-CASPT2 quantum-chemical method and double-ζ basis sets (cc-pVDZ) in gas and condensed phases (1,4-dioxane and water) with the sequential Monte Carlo/CASPT2 and free energy gradient (FEG) methods. Solvation shell structures, in the ground and excited states, were examined with the pairwise radial distribution function (G(r)) and solute-solvent hydrogen-bond networks. Site-specific hydrogen bonding analysis evidenced relevant changes between both electronic states. The three luminescent nucleobases share a common photophysical pattern, summarized as the lowest-lying 1(ππ*) bright state that is populated directly after the absorption of radiation and evolves barrierless to the minimum energy structure, from where the excess of energy is released by fluorescence. From the 1(ππ*)min region, the conical intersection with the ground state ((ππ*/GS)CI) is not accessible due to the presence of high energetic barriers. By combining the present results with those reported earlier by us for the pyrimidine fluorescent nucleobases, we present a comprehensive description of the photophysical properties of this important class of new fluorescent nucleosides.

DICE: A Monte Carlo Code for Molecular Simulation Including the Configurational Bias Monte Carlo Method.

Solute-solvent systems are an important topic of study, as the effects of the solvent on the solute can drastically change its properties. Theoretical studies of these systems are done with ab initio methods, molecular simulations, or a combination of both. The simulations of molecular systems are usually performed with either molecular dynamics (MD) or Monte Carlo (MC) methods. Classical MD has evolved much in the last decades, both in algorithms and implementations, having several stable and efficient codes developed and available. Similarly, MC methods have also evolved, focusing mainly in creating and improving methods and implementations in available codes. In this paper, we provide some enhancements to a configurational bias Monte Carlo (CBMC) methodology to simulate flexible molecules using the molecular fragments concept. In our implementation the acceptance criterion of the CBMC method was simplified and a generalization was proposed to allow the simulation of molecules with any kind of fragments. We also introduce the new version of DICE, an MC code for molecular simulation (available at https://portal.if.usp.br/dice). This code was mainly developed to simulate solute-solvent systems in liquid and gas phases and in interfaces (gas-liquid and solid-liquid) that has been mostly used to generate configurations for a sequential quantum mechanics/molecular mechanics method (S-QM/MM). This new version introduces several improvements over the previous ones, with the ability of simulating flexible molecules with CBMC as one of them. Simulations of well-known molecules, such as n-octane and 1,2-dichloroethane in vacuum and in solution, are presented to validate the new implementations compared with MD simulations, experimental data, and other theoretical results. The efficiency of the conformational sampling was analyzed using the acceptance rates of different alkanes: n-octane, neopentane, and 4-ethylheptane. Furthermore, a very complex molecule, boron subphtalocyanine, was simulated in vacuum and in aqueous solution showing the versatility of the new implementation. We show that the CBMC is a very good method to perform conformation sampling of complex moderately sized molecules (up to 150 atoms) in solution following the Boltzmann thermodynamic equilibrium distribution.

Unraveling the Electric Field-Induced Second Harmonic Generation Responses of Stilbazolium Ion Pairs Complexes in Solution Using a Multiscale Simulation Method.

The electric field-induced second harmonic generation (EFISHG) response has been largely used to describe the first ß and the second γ hyperpolarizabilities in solution. Although the EFISHG technique cannot be applied to charged compounds (due to the external static electric field), it can be used to describe ion pairs as neutral complexes. A multiscale computational approach is required to generate representative geometrical configurations of such kinds of complexes (using classical force fields), to compute the electronic structure of each configuration (using quantum mechanics methods), and to perform statistical analyses describing the behavior of the nonlinear optical properties. In this work, we target solvated neutral ion pairs complexes, of which the cation is an organic chromophore, and we estimate their EFISHG and hyper-Rayleigh scattering responses. It is shown that the anion-cation relative spatial distribution determines the permanent dipole moment of the complexes, and therefore the relative distance controls the EFISHG response. On the other hand, the ß tensor is independent of the dipole moment and it shows a weak linear correlation with the π-electron conjugation length of the cations. The γ contributions in the global EFISHG response range from 5% to 15%, which is mostly due to the variations of amplitude of the µß∥ contribution, which results from differences in the µ and ß vectors' orientations. The applied multiscale approach provides reasonable results compared with experimental ones, although additional efforts are still required to improve such comparison mainly to consider the possible dissociation effects.

Microscopic Origin of Different Hydration Patterns of para-Nitrophenol and Its Anion: A Study Combining Multiconfigurational Calculations and the Free-Energy Gradient Method.

A theoretical study of the solvatochromic shifts of para-nitrophenol ( pNP) and para-nitrophenolate anion ( pNP-) in aqueous solution is presented using a QM/MM methodology with molecular dynamics simulation. The optimized structures in aqueous solution are obtained using both the polarizable continuum and the free-energy gradient methods. For pNP, the calculated redshifts at the CASPT2 (12,10) level are, respectively, 0.71 and 0.94 eV, in good agreement with the experimental ones (0.80-0.83 eV), whereas for pNP-, they are small. The difference between the solvatochromic shifts of pNP and pNP- is calculated as 0.71 eV in good agreement with the experimental one (0.79-0.81 eV). Finally, these shifts are understood in terms of the solvent effect on the solute structure, accurately calculated by the present theoretical treatment.

Theoretical study of the NMR chemical shift of Xe in supercritical condition.

In this work we investigate the level of theory necessary for reproducing the non-linear variation of the 129Xe nuclear magnetic resonance (NMR) chemical shift with the density of Xe in supercritical conditions. In detail we study how the 129Xe chemical shift depends under supercritical conditions on electron correlation, relativistic and many-body effects. The latter are included using a sequential-QM/MM methodology, in which a classical MD simulation is performed first and the chemical shift is then obtained as an average of quantum calculations of 250 MD snapshots conformations carried out for Xe n clusters (n = 2 - 8 depending on the density). The analysis of the relativistic effects is made at the level of 4-component Hartree-Fock calculations (4c-HF) and electron correlation effects are considered using second order Møller-Plesset perturbation theory (MP2). To simplify the calculations of the relativistic and electron correlation effects we adopted an additive scheme, where the calculations on the Xe n clusters are carried out at the non-relativistic Hartree-Fock (HF) level, while electron correlation and relativistic corrections are added for all the pairs of Xe atoms in the clusters. Using this approach we obtain very good agreement with the experimental data, showing that the chemical shift of 129Xe in supercritical conditions is very well described by cluster calculations at the HF level, with small contributions from relativistic and electron correlation effects.

An Average Solvent Electrostatic Configuration Protocol for QM/MM Free Energy Optimization: Implementation and Application to Rhodopsin Systems.

A novel atomistic methodology to perform free energy geometry optimization of a retinal chromophore covalently bound to any rhodopsin-like protein cavity is presented and benchmarked by computing the absorption maxima wavelengths (λmax) of distant rhodopsin systems. The optimization is achieved by computing the Nagaoka's Free Energy Gradient (FEG) within an Average Solvent Electrostatic Configuration (ASEC) atomistic representation of the thermodynamic equilibrium and minimizing such quantity via an iterative procedure based on sequential classical MD and constrained QM/MM geometry optimization steps. The performance of such an ASEC-FEG protocol is assessed at the CASPT2//CASSCF/Amber level by reproducing the λmax values observed for 12 mutants of redesigned human cellular retinol binding protein II (hCRBPII) systems; a set of 10 distant wild-type rhodopsins from vertebrates, invertebrates, eubacteria, and archaea organisms; and finally a set of 10 rhodopsin mutants from an eubacterial rhodopsin. The results clearly show that the proposed protocol, which can be easily extended to any protein incorporating a covalently bound ligand, yields correct λmax trends with limited absolute errors.

Electronic structure and absorption spectra of fluorescent nucleoside analogues.

This work presents a systematic investigation of the electronic and conformational properties of five new fluorescent nucleobases belonging to the alphabet based on the isothiazole[4,3-d]pyrimidine molecule, very recently synthesized. This is of particular importance in the characterization of the main electronic aspects of these fluorescent nucleosides. The solvent effects of 1,4-dioxane and water were included combining the Sequential Monte Carlo/CASPT2 and the Free Energy Gradient (FEG) methods. For comparison, the Polarizable Continuum method was also used. The geometries of all compounds were optimized in solvent with the largest effects observed in water using the average solvent electrostatic configuration (ASEC) and the FEG approaches. Statistical analysis of the solute-solvent hydrogen bonds is performed and their effect on the absorption spectra analyzed. The dipole moments were calculated and the value obtained from the ASEC-FEG method in water follows the same trend as the natural canonical bases (adenine → uracil → guanine → cytosine). The theoretical results for the absorption spectra obtained from CASPT2(18,13) calculations using the geometries obtained with the ASEC-FEG procedure are in very good agreement with the experimental data. A detailed elucidation of the main aspects of the absorption spectra of the five new fluorescent nucleoside analogues is successfully attempted.

Hydration effects on the electronic properties of eumelanin building blocks.

Theoretical results for the electronic properties of eumelanin building blocks in the gas phase and water are presented. The building blocks presently investigated include the monomeric species DHI (5,6-dihydroxyindole) or hydroquinone (HQ), DHICA (5,6-dihydroxyindole-2-carboxylic acid), indolequinone (IQ), quinone methide (MQ), two covalently bonded dimers [HM ≡ HQ + MQ and IM ≡ IQ + MQ], and two tetramers [HMIM ≡ HQ + IM, IMIM ≡ IM + IM]. The electronic properties in water were determined by carrying out sequential Monte Carlo/time dependent density functional theory calculations. The results illustrate the role played by hydrogen bonding and electrostatic interactions in the electronic properties of eumelanin building blocks in a polar environment. In water, the dipole moments of monomeric species are significantly increased ([54-79]%) relative to their gas phase values. Recently, it has been proposed that the observed enhancement of the higher-energy absorption intensity in eumelanin can be explained by excitonic coupling among eumelanin protomolecules [C.-T. Chen et al., Nat. Commun. 5, 3859 (2014)]. Here, we are providing evidence that for DHICA, IQ, and HMIM, the electronic absorption toward the higher-energy end of the spectrum ([180-220] nm) is enhanced by long-range Coulombic interactions with the water environment. It was verified that by superposing the absorption spectra of different eumelanin building blocks corresponding to the monomers, dimers, and tetramers in liquid water, the behaviour of the experimental spectrum, which is characterised by a nearly monotonic decay from the ultraviolet to the infrared, is qualitatively reproduced. This result is in keeping with a "chemical disorder model," where the broadband absorption of eumelanin pigments is determined by the superposition of the spectra associated with the monomeric and oligomeric building blocks.