Owing to their intense near infrared absorption and emission properties, to the ability to photogenerate singlet oxygen, or to act as photoacoustic imaging agents within the optical window of tissue, bacteriochlorins (2,3,12,13-tetrahydroporphyrins) promise to be of utility in many biomedical and technical applications. The ability to fine-tune the electronic properties of synthetic bacteriochlorins is important for these purposes. In this vein, we report the synthesis, structure determination, optical properties, and theoretical analysis of the electronic structure of a family of expanded bacteriochlorin analogues. The stepwise expansion of both pyrroline moieties in near-planar meso-tetraarylbacteriochlorins to morpholine moieties yields ruffled mono- and bismorpholinobacteriochlorins with broadened and up to 90 nm bathochromically shifted bacteriochlorin-like optical spectra. Intramolecular ring-closure reactions of the morpholine moiety with the flanking meso-aryl groups leads to a sharpened, blue-shifted wavelength λmax band, bucking the general red-shifting trend expected for such linkages. A conformational origin of the optical modulations was previously proposed, but discrepancies between the solid state conformations and the corresponding solution state optical spectra defy simple structure-optical property correlations. Using density functional theory and excited state methods, we derive the molecular origins of the spectral modulations. About half of the modulation is due to ruffling of the bacteriochlorin chromophore. Surprisingly, the other half originates in the localized twisting of the Cβ–Cα–Cα–Cβ dihedral angle within the morpholine moieties. Our calculations suggest a predictable and large spectral shift (2.0 nm/deg twist) for morpholine deformations within these fairly flexible moieties. This morpholine moiety deformation can take place largely independently from the overall macrocycle conformation. The morpholinobacteriochlorins are thus excellent models for localized bacteriochlorin chromophore deformations that are suggested to also be responsible for the optical modulation of naturally occurring bacteriochlorophylls. We propose the use of morpholinobacteriochlorins as mechanochromic dyes in engineering and materials science applications.

Thiolated gold nanoclusters (AuNCs), sub-2 nm Au particles capped by Au(I) thiolate complexes, promise to have a myriad of applications in biomedical diagnosis and therapy as well as industrial catalysis, energy production, and monitoring of environmental pollutants. Computational simulations are a valuable tool in elucidating design principles for optimizing application-specific physicochemical properties. However, thiolated AuNCs protected, conjugated, and/or interacting with macromolecules often exceed the limit of computational tractability with present-day quantum chemistry software. To facilitate theoretical studies, a molecular mechanics force field, AuSBio, is presented that reasonably reproduces, and retains, characteristic structural features of perhaps the most intensively studied thiolated AuNC, Au25L18 (L = alkylthiolate), over 2 ns finite temperature molecular dynamics simulations. AuSBio was parametrized within the framework of force fields for (bio)organic simulations to reproduce equilibrium structures and the vibrational density of states for small homoleptic and larger thiolated Au clusters. AuSBio was further validated by the ability to reproduce the experimental structure of Au38L24, as well as bundling of long-chain alkylthiolate ligands, and the nonlinear frequency modulation pattern of a Raman-active vibrational mode, observed experimentally for the Au25 cluster. We envision our AuSBio force field facilitating, in a practical manner, molecular mechanics or hybrid quantum/molecular mechanics simulations on the structure and dynamics of thiolated AuNC bioconjugates and AuNC monolayer-mediated molecular recognition and catalysis events.

Molecular dynamics (MD) simulations were performed to calculate free energies of sorption (ΔGsorb) of cationic aromatic amines to Ca-montmorillonite. We applied the linear interaction energy (LIE) method, well-established in the biochemistry field, to derive ΔGsorb. We obtained a mean average error of 0.3 kcal mol–1 within the compound training set and an error of 0.41 kcal mol–1 for a validation test set. We were able to reproduce absolute ΔGsorb values for a variety of compound structures, including the zwitterionic antibiotic oxytetracycline. MD simulations also provided atomistic level insights into the underlying driving forces that modulate sorption. Importantly, our approach provides a compelling alternative to polyparameter linear free energy relationship methods, which have shown limited success in capturing the sorption of ionogenic compounds with polar and/or charged moieties. We conclude that the LIE method can be used as a robust and tractable method to predict ΔGsorb within families of organic cations bound to aluminosilicate clay minerals.

Au25(SR)18 (R = −CH2–CH2–Ph) is a molecule-like nanocluster displaying distinct electrochemical and optical features. Although it is often taken as an example of a particularly well-understood cluster, very recent literature has provided a quite unclear or even a controversial description of its properties. We prepared monodisperse Au25(SR)180 and studied by cyclic voltammetry, under particularly controlled conditions, the kinetics of its reduction or oxidation to a series of charge states, −2, −1, +1, +2, and +3. For each electrode process, we determined the standard heterogeneous electron-transfer (ET) rate constants and the reorganization energies. The latter points to a relatively large inner reorganization. Reduction to form Au25(SR)182– and oxidation to form Au25(SR)182+ and Au25(SR)183+ are chemically irreversible. The corresponding decay rate constants and lifetimes are incompatible with interpretations of very recent literature reports. The problem of how ET affects the Au25 magnetism was addressed by comparing the continuous-wave electron paramagnetic resonance (cw-EPR) behaviors of radical Au25(SR)180 and its oxidation product, Au25(SR)18+. As opposed to recent experimental and computational results, our study provides compelling evidence that the latter is a diamagnetic species. The DFT-computed optical absorption spectra and density of states of the −1, 0, and +1 charge states nicely reproduced the experimentally estimated dependence of the HOMO–LUMO energy gap on the actual charge carried by the cluster. The conclusions about the magnetism of the 0 and +1 charge states were also reproduced, stressing that the three HOMOs are not virtually degenerate as routinely assumed: In particular, the splitting of the HOMO manifold in the cation species is severe, suggesting that the usefulness of the superatom interpretation is limited. The electrochemical, EPR, and computational results thus provide a self-consistent picture of the properties of Au25(SR)18 as a function of its charge state and may furnish a methodology blueprint for understanding the redox and magnetic behaviors of similar molecule-like gold nanoclusters.

Recent developments in the biophysical characterization of proteins have provided a means of directly measuring electrostatic fields by introducing a probe molecule to the system of interest and interpreting photon absorption in the context of the Stark effect. To fully account for this effect, the development of accurate atomistic models is of paramount importance. However, suitable computational protocols for evaluating Stark shifts in proteins are yet to be established. In this work, we present a comprehensive computational method to predict the change in absorption frequency of a probe functional group as a direct result of a perturbation in its surrounding electrostatic field created by a protein environment, i.e., the Stark shift. We apply the method to human aldose reductase, a key protein enzyme that catalyzes the reduction of monosaccharides. We develop a protocol based on a combination of molecular dynamics and moving-domain QM/MM methods, which achieves quantitative agreement with experiment. We outline the difficulties in predicting localized electrostatic field changes within a protein environment, and by extension the Stark shift, due to a protein site mutation. Furthermore, the combined use of Stark effect spectroscopy and computational modeling is used to predict the protonation state of ionizable residues in the vicinity of the electrostatic probe.

The present work is aimed to provide detail on the binding process between Raf kinase inhibitor protein (RKIP) and locostatin, the only exogenous compound known to alter the function of RKIP. Understanding the basis of RKIP inhibition for use in pharmacological applications is of considerable interest, as dysregulated RKIP expression has the potential to contribute to pathophysiological processes. Herein, we report a series of atomistic models to describe the protein–ligand recognition step and the subsequent reactivity steps. Modeling approaches include ligand docking, molecular dynamics, and quantum mechanics/molecular mechanics calculations. We expect that such a computational assay will serve to study similar complexes in which potency is associated with recognition and reactivity. Although previous data suggested a single amino acid residue (His86) to be involved in the binding of locostatin, the actual ligand conformation and the steps involved in the reactivity process remain elusive from a detailed atomistic description. We show that the first reaction step, consisting of a nucleophilic attack of the nitrogen (Nε) of His86 at the sp2-hybridized carbon (C2) of locostatin, presents a late transition state (almost identical to the product). The reaction is followed by a hydrogen abstraction and hydrolysis. The theoretically predicted overall rate constant (6 M–1 s–1) is in a very good agreement with the experimentally determined rate constant (13 M–1 s–1).

We present a multilevel molecular modeling study aimed at elucidating physical and chemical properties of gold clusters capped by a monolayer of thiolated oligopeptides. The protecting peptides are based on the α-aminoisobutyric acid unit, form intramolecular C═O···H−N bonds, and can form intermolecular hydrogen bonds. This study is motivated by recent breakthroughs into the determination of crystal structures of small gold clusters protected with small thiolated molecules. Such structures are characterized by surface gold atoms in the so-called “staple motifs”, as opposed to the commonly assumed structures in which thiolates bind to a high-symmetry gold cluster. It is unclear, however, whether the staple motif is common to all kinds of protecting layers, especially those made of polypeptides that are largely stabilized by intermolecular hydrogen bonding. Structural and spectroscopic properties are presented to understand the nature of peptide−peptide interactions, their structural arrangements, and their effect on the gold−thiol structural motif.

This work presents new developments of the moving-domain QM/MM (MoD-QM/MM) method for modeling protein electrostatic potentials. The underlying goal of the method is to map the electronic density of a specific protein configuration into a point-charge distribution. Important modifications of the general strategy of the MoD-QM/MM method involve new partitioning and fitting schemes and the incorporation of dynamic effects via a single-step free energy perturbation approach (FEP). Selection of moderately sized QM domains partitioned between \(C_\alpha \) and C (from C=O), with incorporation of delocalization of electrons over neighboring domains, results in a marked improvement of the calculated molecular electrostatic potential (MEP). More importantly, we show that the evaluation of the electrostatic potential can be carried out on a dynamic framework by evaluating the free energy difference between a non-polarized MEP and a polarized MEP. A simplified form of the potassium ion channel protein Gramicidin-A from Bacillus brevis is used as the model system for the calculation of MEP.