Closed-shell d10-d10 mechanochromic [AuPh(CNPh)]n complex: quantum chemistry electronic and optical properties.

The electronic structure, spectroscopic properties, and solid state chemistry of monomer and dimers of [AuPh(CNPh)] complex were studied at post-Hartree-Fock (MP2, SCS-MP2, and CC2) and density functional theory levels. The absorption spectra of these complexes were calculated using single excitation time-dependent (TD) methods at DFT, CC2, and SCS-CC2 levels. The influences of the bulk are accounted for at the PBE-D3 level, incorporating dispersion effects. The calculated values agree with the experimental range, where absorption and emission energies reproduce experimental trends with large Stokes shifts. The aurophilic interaction is identified as a key factor influencing the spectroscopic and structural properties of these complexes. The intermetallic interactions were found as the main factor responsible for MMCT electronic transitions in the models studied.

Is there a Covalent Au(I)-Au(I) Bond in the trans-(AuX)2 (X = F, Cl, Br, I) Structure? A Post-Hartree-Fock and Density Functional Theory Study.

We present an exhaustive exploration of the driving forces dominating the interaction between gold atoms in the trans-(AuX)2, where X is a halogen ligand. This work provides insights into the nature of the gold-gold contact in the trans-(AuX)2. The geometries and energies were calculated at the MP2, CCSD(T), and DFT-D3(BJ) (B3LYP, PBE, and TPSS) levels of theory. The results show a short Au-Au distance, typical of a covalent bond, but with a weak interaction energy associated with noncovalent interactions. It is established that the physical contributions from polarization and the electronic correlation forces are the most relevant at the post-Hartree-Fock level of theory. Also, the electrostatic term is attractive but with low contribution. Finally, the Wiberg indices and NBO analysis exposed a small covalent character between the gold atoms, revealing that this contribution is insufficient to explain the stability of the dimers. It is concluded that a sum of contributions makes it possible to establish an attraction between the gold atoms in the dimers studied beyond a classical aurophilic interaction.

Improving Lurasidone Hydrochloride's Solubility and Stability by Higher-Order Complex Formation with Hydroxypropyl-ß-cyclodextrin.

The biopharmaceutical classification system groups low-solubility drugs into two groups: II and IV, with high and low permeability, respectively. Most of the new drugs developed for common pathologies present solubility issues. This is the case of lurasidone hydrochloride-a drug used for the treatment of schizophrenia and bipolar depression. Likewise, the stability problems of some drugs limit the possibility of preparing them in liquid pharmaceutical forms where hydrolysis and oxidation reactions can be favored. Lurasidone hydrochloride presents the isoindole-1,3-dione ring, which is highly susceptible to alkaline hydrolysis, and the benzisothiazole ring, which is susceptible to a lesser extent to oxidation. Herein, we propose to study the increase in the solubility and stability of lurasidone hydrochloride by the formation of higher-order inclusion complexes with hydroxypropyl-ß-cyclodextrin. Several stoichiometric relationships were studied at between 0.5 and 3 hydroxypropyl-ß-cyclodextrin molecules per drug molecule. The obtained products were characterized, and their solubility and stability were assessed. According to the obtained results, the formation of inclusion complexes dramatically increased the solubility of the drug, and this increased with the increase in the inclusion ratio. This was associated with the loss of crystalline state of the drug, which was in an amorphous state according to infrared spectroscopy, calorimetry, and X-ray analysis. This was also correlated with the stabilization of lurasidone by the cyclodextrin inhibiting its recrystallization. Phase solubility,1H-NMR, and docking computational characterization suggested that the main stoichiometric ratio was 1:1; however, we cannot rule out a 1:2 ratio, where a second cyclodextrin molecule could bind through the isoindole-1,3-dione ring, improving its stability as well. Finally, we can conclude that the formation of higher-order inclusion complexes of lurasidone with hydroxypropyl-ß-cyclodextrin is a successful strategy to increase the solubility and stability of the drug.

Mechanistic insights into the adsorption of endocrine disruptors onto polystyrene microplastics in water.

Microplastics and endocrine disruptors (EDs) are contaminants of emerging concerns and ubiquitously present in aquatic ecosystems, establishing interactions that still are the subject of investigation due to their implications in the cotransport of pollutants. Then, we conducted mechanistic studies based on state-of-art computational chemistry methods to quantitatively understand the interaction mechanisms whereby polystyrene micro or nanoplastics (PS-MPs) interact with representative classes of EDs in water (Ethynylestradiol, Estradiol, and Bisphenol A). The results showed that PS-MPs increase their charge distribution when forming microparticles in water, giving a permanent dipole that explains their increasing solubility in aqueous conditions. In agreement with experimental assessments, the PS-MPs favorably adsorb EDs with adsorption energies larger than 15 kcal/mol, even with comparable stability to nanostructured materials for adsorption, removal, and/or analysis of pollutants. The adsorption occurs via physisorption without covalent binding, bond breaking, or structural preparation energies, where the molecular structure of EDs can favor inner or outer surface adsorption depending on the molecular structure of the adsorbates. A balanced contribution of dispersion and electrostatic stabilizing effects determines the interaction mechanisms, accounting for a whole contribution of 88-90%. The electrostatic contribution emerges from the favorable alignment of the PS-MPs and EDs dipoles upon interaction due to the mild charge transfer between them in solution. In contrast, the dispersion contribution emerges from electron-electron interactions due to the permanent dipoles in adsorbates and adsorbents. Furthermore, thermochemical analyses clarify the role of temperature and pressure effects on the relative adsorption stability among EDs in aquatic environments. Therefore, modeling the adsorption process contributes to new knowledge on the sorption properties of PS-MPs, providing a mechanistic basis to understand the cotransport of pollutants in water environments and their impacts on environmental pollution.

The interaction mechanism of polystyrene microplastics with pharmaceuticals and personal care products.

Microplastics (MPs) have been detected in the hydrosphere, with hazardous implications in transporting coexisting water pollutants. Our knowledge about the interaction mechanisms that MPs establish with organic pollutants are still growing, which is essential to understand the adsorption properties of MPs and their relative stability with adsorbates. Here, we used classical (force field methods) and ab-initio (density functional theory) computational chemistry tools to characterize the interaction mechanisms between Polystyrene-MPs (PS-MPs) and pharmaceuticals/personal care products (PPCPs). Adsorption conformations and energies, thermochemistry, binding, and energy decomposition analyses were performed to obtain the quantitative mechanistic information. Our results show that PS-MPs have permanent dipoles, increasing the interaction with neutral PPCPs while repelling the charged pollutants; in all cases, a stable physisorption takes place. Moreover, PS-MPs increase their solubility upon pollutant adsorption due to an increase in the dipole moment, increasing their co-transport ability in aqueous environments. The stability of the PS-MPs/PPCPs complexes is further confirmed by thermochemical and molecular dynamics trajectory analysis as a function of temperature and pressure. The interaction mechanism of high pKa pollutants (pKa > 5) is due to a balanced contribution of electrostatic and dispersion forces, while the adsorption of low pKa pollutants (pKa < 5) maximizes the electrostatic forces, and steric repulsion effects explain their relative lower adsorption stability. In this regard, several pairwise intermolecular interactions are recognized as a source of stabilization in the PS-MPs/PPCPs binding: hydrogen bonding, π-π, OH⋯π, and CH⋯π, CCl⋯CH and CH⋯CH interactions. The ionic strength in solution slightly affects the adsorption stability of neutral PPCPs, while the sorption of charged pollutants is enhanced. This mechanistic information provides quantitative data for a better understanding of the interactions between organic pollutants and MPs, serving as valuable information for sorption/kinetic studies.

Time-dependent density functional theory studies of the optical and electronic properties of the [M25(MPA)18]- (M = Au, Ag, MPA = SCH2CH2COOH) clusters.

Electronic absorption and emission spectra of [M25(MPA)18]- (M = Au, Ag; MPA = SCH2CH2COOH) clusters have been recorded for energies below 5 eV at the time-dependent density functional theory (TDDFT) level using B3LYP and TPSSh functionals and compared to the calculated ones using the computationally inexpensive simplified TDDFT (sTDDFT) approach. The results show a qualitative agreement between the TDDFT and sTDDFT approaches used here, which were also in line with the experimental and theoretical spectra previously reported. However, the sTDDFT calculations were several orders of magnitude faster than those obtained by TDDFT. Our results support that sTDDFT provides an excellent balance between accuracy and low computational cost, becoming a suitable approach for studying the absorption and emission spectra of noble-metal clusters of sizes that would be unaffordable by the traditional TDDFT methods. The main peaks of the experimental absorption spectrum of [Au25(MPA)18]- have been previously assigned, whereas [Ag25(MPA)18]- has not been synthesised. However, its absorption spectrum resulted in having similar features to the experimental spectrum of [Ag25(GSH)18]- (GSH = glutathione), used to validate our results. The emission spectra, which to date have not been reported either from experimental or theoretical means, were simulated by using the molecular structure of the first excited triplet state (T1). The emission spectra were obtained by comparing them to those of [M25(GSH)18]- since no experimental luminescence spectra have been reported for [M25(MPA)18]-. The calculations suggest that [Ag25(SR)18]- (SR = thiolate) clusters have a weak luminescence band in the NIR region. Finally, solvent shifts were found to be minor, whereas the absorption bands seem to be significantly redshifted in solid-state materials.

Unraveling the Role of the Tyrosine Tetrad from the Binding Site of the Epigenetic Writer MLL3 in the Catalytic Mechanism and Methylation Multiplicity.

MLL3, also known as KMT2C, is a lysine mono-methyltransferase in charge of the writing of an epigenetic mark on lysine 4 from histone 3. The catalytic site of MLL3 is composed of four tyrosines, namely, Y44, Y69, Y128, and Y130. Tyrosine residues are highly conserved among lysine methyltransferases' catalytic sites, although their complete function is still unclear. The exploration of how modifications on these residues from the enzymatic machinery impact the enzymatic activity of MLL3 could shed light transversally into the inner functioning of enzymes with similar characteristics. Through the use of QMMM calculations, we focus on the effect of the mutation of each tyrosine from the catalytic site on the enzymatic activity and the product specificity in the current study. While we found that the mutations of Y44 and Y128 by phenylalanine inactivated the enzyme, the mutation of Y128 by alanine reactivated the enzymatic activity of MLL3. Moreover, according to our models, the Y128A mutant was even found to be capable of di- and tri-methylate lysine 4 from histone 3, what would represent a gain of function mutation, and could be responsible for the development of diseases. Finally, we were able to establish the inactivation mechanism, which involved the use of Y130 as a water occlusion structure, whose conformation, once perturbed by its mutation or Y128 mutant, allows the access of water molecules that sequester the electron pair from lysine 4 avoiding its methylation process and, thus, increasing the barrier height.

Closed-shell d10-d10 in [AuCl(CNR)] n and [AuCl(CO)] n (n = 1, 2; R = -H, -CH3, -Cy) complexes: quantum chemistry study of their electronic and optical properties.

The electronic structure and spectroscopic properties of [AuCl(CNR)] and [AuCl(CO)] (R = -H, -CH3, -Cy) complexes with d10-d10 type interactions were studied at the post-Hartree-Fock (MP2, SCS-MP2, CCSD(T)) and density functional theory levels. It was found that the nature of the intermetal interactions is consistent with the presence of an electrostatic (dipole-dipole) contribution and a dispersion-type interaction. The absorption spectra of these complexes were calculated using the single excitation time-dependent (TD) method at the DFT and SCS-CC2 levels. The calculated values are in agreement with the experimental range, where the absorption and emission energies reproduce the experimental trends, with large Stokes shifts. According to this, intermetallic interactions were found to be mainly responsible for the metal-metal charge transfer (MMCT) electronic transitions among the models studied.

Biochemical characterization of Peumus boldus fruits: Insights of its antioxidant properties through a theoretical approach.

Peumus boldus is an endemic tree species from Chile whose leaves have been the focus of study for decades given that their infusions are reported to relieve rheumatic symptoms, headache, dyspepsia, urinary tract inflammation, and symptoms of other illnesses. These health properties have been studied mainly using leaves and bark, then it is relevant to know more about these properties in different parts of the plant. Considering the importance of P. boldus fruits in the diet of some rural populations, we analyzed their properties to explore its impact on the Chilean population health. Liquid chromatography and mass spectrometry analysis confirmed the presence of alkaloids such as boldine, although aporphine N-methyl-laurotetanine was the most abundant. In addition, flavonoids catechin, chrysin and quercetin were also found in the extract. Cytotoxicity and anti-inflammatory activities of the fruit extract were invitro tested by using a murine macrophage cell model, observing that a diluted fraction of the extract was not cytotoxic, but showed anti-inflammatory activity, which is likely attributed to antioxidants activities. By means of quantum chemical calculations, we calculated the redox potential of the respective alkaloids and flavonoids found in the extract. Results suggest a synergistic effect between alkaloids and flavonoids, where boldine and N-methyl-laurotetanine showed similar antioxidant properties. Finally, we present a description of the oxidation mechanisms for both groups of molecules which will sustain P. boldus fruit biological properties, in order to give this kind of fruits scientific value focusing on human health.

Exploration of the Activation Mechanism of the Epigenetic Regulator MLL3: A QM/MM Study.

The mixed lineage leukemia 3 or MLL3 is the enzyme in charge of the writing of an epigenetic mark through the methylation of lysine 4 from the N-terminal domain of histone 3 and its deregulation has been related to several cancer lines. An interesting feature of this enzyme comes from its regulation mechanism, which involves its binding to an activating dimer before it can be catalytically functional. Once the trimer is formed, the reaction mechanism proceeds through the deprotonation of the lysine followed by the methyl-transfer reaction. Here we present a detailed exploration of the activation mechanism through a QM/MM approach focusing on both steps of the reaction, aiming to provide new insights into the deprotonation process and the role of the catalytic machinery in the methyl-transfer reaction. Our finding suggests that the source of the activation mechanism comes from conformational restriction mediated by the formation of a network of salt-bridges between MLL3 and one of the activating subunits, which restricts and stabilizes the positioning of several residues relevant for the catalysis. New insights into the deprotonation mechanism of lysine are provided, identifying a valine residue as crucial in the positioning of the water molecule in charge of the process. Finally, a tyrosine residue was found to assist the methyl transfer from SAM to the target lysine.

Exploration of the Interaction Strength at the Interface of Anionic Chalcogen Anchors and Gold (111)-Based Nanomaterials.

Nowadays, the use of sulfur-based ligands to modify gold-based materials has become a common trend. Here, we present a theoretical exploration of the modulation of the chalcogenides-gold interaction strength, using sulfur, selenium, and tellurium as anchor atoms. To characterize the chalcogenide-gold interaction, we designed a nanocluster of 42 gold atoms (Au42) to model a gold surface (111) and a series of 60 functionalized phenyl-chalcogenolate ligands to determine the ability of electron-donor and -withdrawing groups to modulate the interaction. The analysis of the interaction was performed by using energy decomposition analysis (EDA), non-covalent interactions index (NCI), and natural population analysis (NPA) to describe the charge transfer processes and to determine data correlation analyses. The results revealed that the magnitudes of the interaction energies increase following the order S < Se < Te, where this interaction strength can be augmented by electron-donor groups, under the donor-acceptor character the chalcogen-gold interaction. We also found that the functionalization in meta position leads to better control of the interaction strength than the ortho substitution due to the steric and inductive effects involved when functionalized in this position.

Theoretical exploration of the forces governing the interaction between gold-phthalocyanine and gold surface clusters.

Here we aim to explore the nature of the forces governing the adsorption of gold-phthalocyanine on gold substrates. For this, we designed computational models of metal-free phthalocyanine and gold-phthalocyanine deposited over a gold metallic surface represented by cluster models of different sizes and geometries. Thereby, we were able to determine the role of the metal center and of the size of the substrate in the interaction process. For this purpose, we worked within the framework provided by density functional theory, were the inclusion of the semi-empirical correction of the dispersion forces of Grimme's group was indispensable. It has been shown that the interaction between molecules and surfaces is ruled by van der Waals attractive forces, which determine the stabilization of the studied systems and their geometric properties. Their contribution was characterized by energy decomposition analysis and through the visualization of the dispersion interactions by means of the NCI methodology. Moreover, calculations of Density of States (DOS) showed that the molecule-surface system displays a metal-organic interface evidenced by changes in their electronic structure, in agreement with a charge transfer process found to take place between the interacting parts.

Electronic and optical properties of [Au(CH3CSS)]4 cluster. A quantum chemistry study.

The uses of the sulfur-gold bond in the design of new molecular clusters have gained increasing attention in recent years. Their size and shape are diverse providing a wide variety of optical and electronic properties. Here we present a computational study of the absorption and emission properties of a small [Au(dithioacetate)]4 cluster as a model for these systems. The electronic structure of the Au4S8 core of this cluster permits rationalization of the source of the optical properties and how these are connected with that specific structural scaffold. Due to the complex nature of the aurophilic intramolecular interactions taking place in this system, several methods were used, such as the MP2, SCS-MP2, PBE-D3, and TPSS-D3 levels; both in gas and solvent phases. The absorption spectra of the cluster were calculated by the single excitation time-dependent-DFT (TD-DFT) method, CC2, SCS-CC2, and ADC(2) levels. The ab initio correlated calculations and previously reported experimental data have been used to assess the performance of our calculations. Moreover, the emission T1-So transition was calculated, where the SCS-CC2 level showed an excellent agreement with the experimental results. The core Au4S8 was identified as mainly responsible for the absorption and emission transitions according to the theoretical model.

Oxidized and Si-doped graphene: emerging adsorbents for removal of dioxane.

Graphene-based materials have emerged as new potential adsorbents for the adsorption and removal of persistent pollutants, and they could play a key role in the remediation of 1,4-dioxane. In this framework, a quantum chemistry study was carried out to rationalize the sorption properties of oxidized graphene (GO) and Si-doped graphene (SiG) nanosheets for use in 1,4-dioxane removal, taking into account that these adsorbents are experimentally available. Dispersion corrected PBE-D3/SVP calculations show that GO and SiG adsorbs dioxane through non-covalent and covalent interactions, respectively, with adsorption energies of up to ∼0.9 eV, which represents an important improvement with respect to the adsorption onto intrinsic graphene. The adsorption strength was also rationalized in terms of natural bond orbitals, atoms-in-molecules and energy decomposition analyses. In the case of GO, a high content of hydroxyl and carboxyl functional groups enhances the removal efficiency, and they are responsible for the high adsorption stability in aqueous environments and at room temperature (300 K). In addition, explicit/implicit solvent calculations and molecular dynamics trajectories show that the SiG-dioxane interaction is highly stable at 300 K, without pollutant diffusion; besides, the SiG-dioxane interaction is stabilized in the presence of H2O molecules. All the analyses suggest that GO and SiG should be considered as new remarkable candidates for sorption technologies related to the removal, control and remediation of 1,4-dioxane, where the sorption efficiency is sorted as SiG > GO ≫ G.

Adsorption/desorption process of formaldehyde onto iron doped graphene: a theoretical exploration from density functional theory calculations.

The interaction of formaldehyde (H2CO) onto Fe-doped graphene (FeG) was studied in detail from density functional theory calculations and electronic structure analyses. Our aim was to obtain insights into the adsorption, desorption and sensing properties of FeG towards H2CO, a hazardous organic compound. The adsorption of H2CO was shown to be energetically stable onto FeG, with adsorption energies of up to 1.45 eV and favored in different conformations. This interaction was determined to be mostly electrostatic in nature, where the oxygen plays an important role in this contribution; besides, our quantum molecular dynamics results showed the high stability of the FeG-H2CO interaction at ambient temperature (300 K). All the interactions were determined to be accompanied by an increase in the HOMO-LUMO energy gap with respect to the isolated adsorbent, indicating that FeG is highly sensitive to H2CO with respect to pristine graphene. Finally, it was found that external electric fields of 0.04-0.05 a.u. were able to induce the pollutant desorption from the adsorbent, allowing the adsorbent reactivation for repetitive applications. These results indicate that FeG could be a promising candidate for adsorption/sensing platforms of H2CO.

Catalytic aspects of metallophthalocyanines adsorbed on gold-electrode. Theoretical exploration of the binding nature role.

The need of deeper insights regarding the inner working of catalysts represents a current challenge in the search of new ways to tune their activities towards new chemical transformations. Within this field, metallophthalocyanines-based (MPc) electrocatalysis has gained tremendous attention due to their versatility, low cost, great stability and excellent turn-over properties. In this concern, here we present a quantum chemical study of the formation of supramolecular complexes based on the adsorption of MPcs on gold substrates, and the effect of the substrate on their electrocatalytic properties. For this purpose, we used iron- (FePc), cobalt- (CoPc) and copper-phthalocyanines (CuPc). To model the gold surface we used two gold clusters of different sizes, given by Au26 and Au58 accounting for gold electrode Au(111) surface. Thus, both electronic and binding strength features of the adsorption process between the complexes were analyzed in detail in order to gain a deeper description of the nature of the MPc-Au(111) formation, by using Density Functional Theory (DFT) calculations, at the PBE and TPSS levels including the dispersive contribution according to the Grimme approach (D3). Our results show that dispersion forces rule the MPc-gold interaction, with binding strengths ranging between 61 and 153 kcal mol-1, in agreement to the reported experimental data. To provide a detailed picture of our findings we used the non-covalent interactions index (NCIs) analysis, which offers additional chemical insights regarding the forces that control their interaction strength. Finally, our calculations revealed that among the three MPcs, CuPc required less energy for its oxidation. However, the removal of the electron involves a tremendous decrease of the MPc-gold surface interaction strength thus suggesting its desorption, which would prevent the required reversibility of the redox reaction, explaining its low performance observed experimentally.

Theoretical study on interactions of fluorinated organomercurials with arene and gold fragments.

The electronic structure and spectroscopic properties of [Hg(C6F5)2]2-{L}, [Hg3(o-C6F4)3]2·{L} (L = naphthalene, biphenyl, fluorene) and [Hg3(o-C6F4)3]{Au3(µ-C(OEt)=NC6H4CH3)3}n (n = 1, 2) adducts were studied at the HF, MP2, SCS-MP2, DFT and DFT-D3 levels. The intermolecular interactions among the fragments were analyzed using the levels of calculations proposed. The energy decomposition analysis at the TPSS-D3 level was used to define the dominant components of the interaction. The van der Waals interactions between mercury and arene (Hg-arene) were found to be the main short-range stability contribution in the [Hg(C6F5)2]2-{L} and [Hg3(o-C6F4)3]2·{L} complexes. At the MP2, SCS-MP2 and DFT-D3 levels, equilibrium Hg-C distances are between 360 and 310 pm. The pair-wise energies were found to be between 18.0 and 6.0 kJ mol(-1). In the [Hg3(o-C6F4)3]{Au3(µ-C(OEt)=NC6H4CH3)3}n (n = 1, 2) complexes the metallophilic intermolecular interaction is Hg-Au. Pair-wise energies of 85.7, 39.4, 78.1 and 57.9 kJ mol(-1) were found at the MP2, SCS-MP2, TPSS-D3 and PBE-D3 levels using the [Hg3(o-C6F4)3]{Au3(µ-C(OEt)=NC6H4CH3)3} model. The same trend is maintained for the [Hg3(o-C6F4)3]{Au3(µ-C(OEt)=NC6H4CH3)3}2 model: 73.4, 29.3, 70.6 and 61.3 kJ mol(-1) by MP2, SCS-MP2, TPSS-D3 and PBE-D3, respectively. The absorption spectra of these complexes were calculated using the single excitation time-dependent method at the TPSS-D3 level to validate the models against the experimental data.

Mechanistic insights into the dehalogenation reaction of fluoroacetate/fluoroacetic acid.

Fluoroacetate is a toxic compound whose environmental accumulation may represent an important contamination problem, its elimination is therefore a challenging issue. Fluoroacetate dehalogenase catalyzes its degradation through a two step process initiated by an S(N)2 reaction in which the aspartate residue performs a nucleophilic attack on the carbon bonded to the fluorine; the second step is hydrolysis that releases the product as glycolate. In this paper, we present a study based on density functional theory calculations of the S(N)2 initiation reaction modeled through the interaction between the substrate and the propionate anion as the nucleophile. Results are analyzed within the framework of the reaction force and using the reaction electronic flux to identify and characterize the electronic activity that drives the reaction. Our results reveal that the selective protonation of the substrate catalyzes the reaction by decreasing the resistance of the structural and electronic reorganization needed to reach the transition state. Finally, the reaction energy is modulated by the degree of stabilization of the fluoride anion formed after the S(N)2 reaction. In this way, a site-induced partial protonation acts as a chemical switch in a key process that determines the output of the reaction.

Influence of protonation on substrate and inhibitor interactions at the active site of human monoamine oxidase-A.

Although substrate conversion mediated by human monoaminooxidase (hMAO) has been associated with the deprotonated state of their amine moiety, data regarding the influence of protonation on substrate binding at the active site are scarce. Thus, in order to assess protonation influence, steered molecular dynamics (SMD) runs were carried out. These simulations revealed that the protonated form of the substrate serotonin (5-HT) exhibited stronger interactions at the protein surface compared to the neutral form. The latter displayed stronger interactions in the active site cavity. These observations support the possible role of the deprotonated form in substrate conversion. Multigrid docking studies carried out to rationalize the role of 5-HT protonation in other sites besides the active site indicated two energetically favored docking sites for the protonated form of 5-HT on the enzyme surface. These sites seem to be interconnected with the substrate/inhibitor cavity, as revealed by the tunnels observed by means of CAVER program. pK(a) calculations in the surface loci pointed to Glu³²7, Asp³²8, His488, and Asp¹³² as candidates for a possible in situ deprotonation step. Docking analysis of a group of inhibitors (structurally related to substrates) showed further interactions with the same two docking access sites. Interestingly, the protonated/deprotonated amine moiety of almost all compounds attained different docking poses in the active site, none of them oriented to the flavin moiety, thus producing a more variable and less productive orientations to act as substrates. Our results highlight the role of deprotonation in facilitating substrate conversion and also might reflect the necessity of inhibitor molecules to adopt specific orientations to achieve enzyme inhibition.

Computational studies of the metal-binding site of the wild-type and the H46R mutant of the copper, zinc superoxide dismutase.

Impairment of the Zn(II)-binding site of the copper, zinc superoxide dismutase (CuZnSOD) protein is involved in a number of hypotheses and explanations for the still unknown toxic gain of function mutant varieties of CuZnSOD that are associated with familial forms of amyotrophic lateral sclerosis (ALS). In this work, computational chemistry methods have been used for studying models of the metal-binding site of the ALS-linked H46R mutant of CuZnSOD and of the wild-type variety of the enzyme. By comparing the energy and electronic structure of these models, a plausible explanation for the effect of the H46R mutation on the zinc site is obtained. The computational study clarifies the role of the D124 and D125 residues for keeping the structural integrity of the Zn(II)-binding site, which was known to exist but its mechanism has not been explained. Earlier results suggest that the explanation for the impairment of the Zn(II)-site proposed in this work may be useful for understanding the mechanism of action of the ALS-linked mutations in CuZnSOD in general.