Computational Spectroscopy of Aqueous Solutions: The Underlying Role of Conformational Sampling.

Fully atomistic multiscale polarizable quantum mechanics (QM)/molecular mechanics (MM) approaches, combined with techniques to sample the solute-solvent phase space, constitute the most accurate method to compute spectral signals in aqueous solution. Conventional sampling strategies, such as classical molecular dynamics (MD), may encounter drawbacks when the conformational space is particularly complex, and transition barriers between conformers are high. This can lead to inaccurate sampling, which can potentially impact the accuracy of spectral calculations. For this reason, in this work, we compare classical MD with enhanced sampling techniques, i.e., replica exchange MD and metadynamics. In particular, we show how the different sampling techniques affect computed UV, electronic circular dichroism, nuclear magnetic resonance shielding, and optical rotatory dispersion of N-acetylproline-amide in aqueous solution. Such a system is a model peptide characterized by complex conformational variability. Calculated values suggest that spectral properties are influenced by solute conformers, relative population, and solvent effects; therefore, particular care needs to be paid for when choosing the sampling technique.

Time-Dependent Multilevel Density Functional Theory.

We present a novel three-layer approach based on multilevel density functional theory (MLDFT) and polarizable molecular mechanics to simulate the electronic excitations of chemical systems embedded in an external environment within the time-dependent DFT formalism. In our method, the electronic structure of a target system, the chromophore, is determined in the field of an embedded inactive layer, which is treated as frozen. Long-range interactions are described by employing the polarizable fluctuating charge (FQ) force field. The resulting MLDFT/FQ thus accurately describes both electrostatics (and polarization) and non-electrostatic target-environment interactions. The robustness and reliability of the approach are demonstrated by comparing our results with experimental data reported for various organic molecules in solution.

Close-Up Look at Electronic Spectroscopic Signatures of Common Pharmaceuticals in Solution.

Simulating electronic properties and spectral signals requires robust computational approaches that need tuning with the system's peculiarities. In this paper, we test implicit and fully atomistic solvation models for the calculation of UV-vis and electronic circular dichroism (ECD) spectra of two pharmaceutically relevant molecules, namely, (2S)-captopril and (S)-naproxen, dissolved in aqueous solution. Room temperature molecular dynamics simulations reveal that these two drugs establish strong contacts with the surrounding solvent molecules via hydrogen bonds. Such specific interactions, which play a major role in the spectral response and are neglected in implicit approaches, are further characterized and quantified with natural bond orbital methods. Our calculations show that simulated spectra, and especially ECD, are in good agreement with experiments solely when conformational and configurational dynamics, mutual polarization, and solute-solvent repulsion effects are considered.

Multiscale Frozen Density Embedding/Molecular Mechanics Approach for Simulating Magnetic Response Properties of Solvated Systems.

We present a three-layer hybrid quantum mechanical/quantum embedding/molecular mechanics approach for calculating nuclear magnetic resonance (NMR) shieldings and J-couplings of molecular systems in solution. The model is based on the frozen density embedding (FDE) and polarizable fluctuating charges (FQ) and fluctuating dipoles (FQFµ) force fields and permits the accurate ab initio description of short-range nonelectrostatic interactions by means of the FDE shell and cost-effective treatment of long-range electrostatic interactions through the polarizable force field FQ(Fµ). Our approach's accuracy and potential are demonstrated by studying NMR spectra of Brooker's merocyanine in aqueous and nonaqueous solutions.

Computational Insights into the Adsorption of Ligands on Gold Nanosurfaces.

We study the adsorption process of model peptides, nucleobases, and selected standard ligands on gold through the development of a computational protocol based on fully atomistic classical molecular dynamics (MD) simulations combined with umbrella sampling techniques. The specific features of the interface components, namely, the molecule, the metallic substrate, and the solvent, are taken into account through different combinations of force fields (FFs), which are found to strongly affect the results, especially changing absolute and relative adsorption free energies and trends. Overall, noncovalent interactions drive the process along the adsorption pathways. Our findings also show that a suitable choice of the FF combinations can shed light on the affinity, position, orientation, and dynamic fluctuations of the target molecule with respect to the surface. The proposed protocol may help the understanding of the adsorption process at the microscopic level and may drive the in-silico design of biosensors for detection purposes.

QM/Classical Modeling of Surface Enhanced Raman Scattering Based on Atomistic Electromagnetic Models.

We present quantum mechanics (QM)/frequency dependent fluctuating charge (QM/ωFQ) and fluctuating dipoles (QM/ωFQFµ) multiscale approaches to model surface-enhanced Raman scattering spectra of molecular systems adsorbed on plasmonic nanostructures. The methods are based on a QM/classical partitioning of the system, where the plasmonic substrate is treated by means of the atomistic electromagnetic models ωFQ and ωFQFµ, which are able to describe in a unique fashion and at the same level of accuracy the plasmonic properties of noble metal nanostructures and graphene-based materials. Such methods are based on classical physics, i.e. Drude conduction theory, classical electrodynamics, and atomistic polarizability to account for interband transitions, by also including an ad-hoc phenomenological correction to describe quantum tunneling. QM/ωFQ and QM/ωFQFµ are thus applied to selected test cases, for which computed results are compared with available experiments, showing the robustness and reliability of both approaches.

Continuum vs. atomistic approaches to computational spectroscopy of solvated systems.

Molecular spectral signals can be significantly altered by solvent effects. Among the many theoretical approaches to this problem, continuum and atomistic solvation models have emerged as the most effective for properly describing solvent effects on the spectroscopic signal. In this feature article, we review the continuum and atomistic descriptions as applied to the calculation of molecular spectra, by detailing the similarities and differences between the two approaches from the formal point of view and by analyzing their advantages and disadvantages from the computational point of view. Various spectral signals, of increasing complexity, are considered and illustrative examples, selected to exacerbate the differences between the two approaches, are discussed.

Correction to "Going Beyond the Limits of Classical Atomistic Modeling of Plasmonic Nanostructures".

[This corrects the article DOI: 10.1021/acs.jpcc.1c04716.].

Water Maintains the UV-Vis Spectral Features During the Insertion of Anionic Naproxen and Ibuprofen into Model Cell Membranes.

UV-vis spectra of anionic ibuprofen and naproxen in a model lipid bilayer of the cell membrane are investigated using computational techniques in combination with a comparative analysis of drug spectra in purely aqueous environments. The simulations aim at elucidating the intricacies behind the negligible changes in the maximum absorption wavelength in the experimental spectra. A set of configurations of the systems constituted by lipid, water, and drugs or just water and drugs are obtained from classical Molecular Dynamics simulations. UV-vis spectra are computed in the framework of atomistic Quantum Mechanical/Molecular Mechanics (QM/MM) approaches together with Time-Dependent Density Functional Theory (TD-DFT). Our results suggest that the molecular orbitals involved in the electronic transitions are the same, regardless of the chemical environment. A thorough analysis of the contacts between the drug and water molecules reveals that no significant changes in UV-vis spectra are a consequence of ibuprofen and naproxen molecules being permanently microsolvated by water molecules, despite the presence of lipid molecules. Water molecules microsolvate the charged carboxylate group as expected but also microsolvate the aromatic regions of the drugs.

Strain-Induced Plasmon Confinement in Polycrystalline Graphene.

Terahertz spectroscopy is a perfect tool to investigate the electronic intraband conductivity of graphene, but a phenomenological model (Drude-Smith) is often needed to describe disorder. By studying the THz response of isotropically strained polycrystalline graphene and using a fully atomistic computational approach to fit the results, we demonstrate here the connection between the Drude-Smith parameters and the microscopic behavior. Importantly, we clearly show that the strain-induced changes in the conductivity originate mainly from the increased separation between the single-crystal grains, leading to enchanced localization of the plasmon excitations. Only at the lowest strain values explored, a behavior consistent with the deformation of the individual grains can instead be observed.

UV-Resonance Raman Spectra of Systems in Complex Environments: A Multiscale Modeling Applied to Doxorubicin Intercalated into DNA.

UV-Resonance Raman (RR) spectroscopy is a valuable tool to study the binding of drugs to biomolecular receptors. The extraction of information at the molecular level from experimental RR spectra is made much easier and more complete thanks to the use of computational approaches, specifically tuned to deal with the complexity of the supramolecular system. In this paper, we propose a protocol to simulate RR spectra of complex systems at different levels of sophistication, by exploiting a quantum mechanics/molecular mechanics (QM/MM) approach. The approach is challenged to investigate RR spectra of a widely used chemotherapy drug, doxorubicin (DOX) intercalated into a DNA double strand. The computed results show good agreement with experimental data, thus confirming the reliability of the computational protocol.

Integrated Multiscale Multilevel Approach to Open Shell Molecular Systems.

We present a novel multiscale approach to study the electronic structure of open shell molecular systems embedded in an external environment. The method is based on the coupling of multilevel Hartree-Fock (MLHF) and Density Functional Theory (MLDFT), suitably extended to the unrestricted formalism, to Molecular Mechanics (MM) force fields (FF). Within the ML region, the system is divided into active and inactive parts, thus describing the most relevant interactions (electrostatic, polarization, and Pauli repulsion) at the quantum level. The surrounding MM part, which is formulated in terms of nonpolarizable or polarizable FFs, permits a physically consistent treatment of long-range electrostatics and polarization effects. The approach is extended to the calculation of hyperfine coupling constants and applied to selected nitroxyl radicals in an aqueous solution.

Multiple Facets of Modeling Electronic Absorption Spectra of Systems in Solution.

In this Perspective, we outline the essential physicochemical aspects that need to be considered when building a reliable approach to describe absorption properties of solvated systems. In particular, we focus on how to properly model the complexity of the solvation phenomenon, arising from dynamical aspects and specific, strong solute-solvent interactions. To this end, conformational and configurational sampling techniques, such as Molecular Dynamics, have to be coupled to accurate fully atomistic Quantum Mechanical/Molecular Mechanics (QM/MM) methodologies. By exploiting different illustrative applications, we show that an effective reproduction of experimental spectral signals can be achieved by delicately balancing exhaustive sampling, hydrogen bonding, mutual polarization, and nonelectrostatic effects.

Assessing the quality of QM/MM approaches to describe vacuo-to-water solvatochromic shifts.

The performance of different quantum mechanics/molecular mechanics embedding models to compute vacuo-to-water solvatochromic shifts is investigated. In particular, both nonpolarizable and polarizable approaches are analyzed and computed results are compared to reference experimental data. We show that none of the approaches outperform the others and that errors strongly depend on the nature of the molecular transition to be described. Thus, we prove that the best choice of embedding model highly depends on the molecular system and that the use of a specific approach as a black box can lead to significant errors and, sometimes, totally wrong predictions.

Linear response properties of solvated systems: a computational study.

We present a computational study of static and dynamic linear polarizabilities in solution. We use different theoretical approaches to describe solvent effects, ranging from quantum mechanics/molecular mechanics (QM/MM) to quantum embedding approaches. In particular, we consider non-polarizable and polarizable QM/MM methods, the latter based on the fluctuating charge (FQ) force field. In addition, we use a quantum embedding method defined in the context of multilevel Hartree-Fock (MLHF), where the system is divided into active and inactive regions, and combine it with a third layer described by means of the FQ model. The multiscale approaches are then used as reference wave functions for equation-of-motion coupled cluster (EOM-CC) response properties, allowing for the account of electron correlation. The developed models are applied to the calculation of linear response properties of two organic moieties-namely, para-nitroaniline and benzonitrile-in non-aqueous solvents-1,4-dioxane, acetonitrile, and tetrahydrofuran. The computed polarizabilities are then discussed in terms of the physico-chemical solute-solvent interactions described by each method (electrostatic, polarization and Pauli repulsion), and finally compared with the available experimental references.

Do We Really Need Quantum Mechanics to Describe Plasmonic Properties of Metal Nanostructures?

Optical properties of metal nanostructures are the basis of several scientific and technological applications. When the nanostructure characteristic size is of the order of few nm or less, it is generally accepted that only a description that explicitly describes electrons by quantum mechanics can reproduce faithfully its optical response. For example, the plasmon resonance shift upon shrinking the nanostructure size (red-shift for simple metals, blue-shift for d-metals such as gold and silver) is universally accepted to originate from the quantum nature of the system. Here we show instead that an atomistic approach based on classical physics, ωFQFµ (frequency dependent fluctuating charges and fluctuating dipoles), is able to reproduce all the typical "quantum" size effects, such as the sign and the magnitude of the plasmon shift, the progressive loss of the plasmon resonance for gold, the atomistically detailed features in the induced electron density, and the non local effects in the nanoparticle response. To support our findings, we compare the ωFQFµ results for Ag and Au with literature time-dependent DFT simulations, showing the capability of fully classical physics to reproduce these TDDFT results. Only electron tunneling between nanostructures emerges as a genuine quantum mechanical effect, that we had to include in the model by an ad hoc term.

Fragment Localized Molecular Orbitals.

We introduce the concept of fragment localized molecular orbitals (FLMOs), which are Hartree-Fock molecular orbitals localized in specific fragments constituting a molecular system. In physical terms, we minimize the local electronic energies of the different fragments, at the cost of maximizing the repulsion between them. To showcase the approach, we rationalize the main interactions occurring in large biological systems in terms of interactions between the fragments of the system. In particular, we study an anticancer drug intercalated within DNA and retinal in anabaena sensory rhodopsin as prototypes of molecular systems embedded in biological matrixes. Finally, the FLMOs are exploited to rationalize the formation of two oligomers, prototypes of amyloid diseases, such as Parkinson and Alzheimer.

Amide Spectral Fingerprints are Hydrogen Bonding-Mediated.

The origin of the peculiar amide spectral features of proteins in aqueous solution is investigated, by exploiting a combined theoretical and experimental approach to study UV Resonance Raman (RR) spectra of peptide molecular models, namely N-acetylglycine-N-methylamide (NAGMA) and N-acetylalanine-N-methylamide (NALMA). UVRR spectra are recorded by tuning Synchrotron Radiation at several excitation wavelengths and modeled by using a recently developed multiscale protocol based on a polarizable QM/MM approach. Thanks to the unparalleled agreement between theory and experiment, we demonstrate that specific hydrogen bond interactions, which dominate hydration dynamics around these solutes, play a crucial role in the selective enhancement of amide signals. These results further argue the capability of vibrational spectroscopy methods as valuable tools for refined structural analysis of peptides and proteins in aqueous solution.

In silico design of graphene plasmonic hot-spots.

We propose a route for the rational design of engineered graphene-based nanostructures, which feature enormously enhanced electric fields in their proximity. Geometrical arrangements are inspired by nanopatterns allowing single molecule detection on noble metal substrates, and are conceived to take into account experimental feasibility and ease in fabrication processes. The attention is especially focused on enhancement effects occurring close to edge defects and grain boundaries, which are usually present in graphene samples. There, very localized hot-spots are created, with enhancement factors comparable to noble metal substrates, thus potentially paving the way for single molecule detection from graphene-based substrates.

Absorption Properties of Large Complex Molecular Systems: The DFTB/Fluctuating Charge Approach.

We report on the first formulation of a novel polarizable QM/MM approach, where the density functional tight binding (DFTB) is coupled to the fluctuating charge (FQ) force field. The resulting method (DFTB/FQ) is then extended to the linear response within the TD-DFTB framework and challenged to study absorption spectra of large condensed-phase systems.