Quantum Mechanics/molecular Mechanics Research Articles

Electronic and photolytic properties of hydridocobalamin.

Hydridocobalamin (HCbl), is a known member of the B12 family of molecules (cobalamins, Cbls) yet unlike other well-studied Cbls, little is known of the electronic and photolytic properties of this species. Interest in HCbl has increased significantly in recent years when at least three experimentally proposed mechanisms implicate HCbl as an intermediary in the photoreaction of coenzyme B12-dependent photoreceptor CarH. Specifically, cleavage of the Co-C5' bond of coenzyme B12 could lead to a β-hydride or β‑hydrogen elimination reaction to form HCbl. HCbl is known to be a transient species where the oxidation state of the Co is variable; Co(I)-H+ ↔ Co(II)-H↔Co(III)-H-. Further, HCbl is a very unstable with a pKa of ~1. This complicates experimental studies and to the best of our knowledge there are no available crystal structures of HCbl - either for the isolated molecule or bound to an enzyme. In this study, the electronic structure, photolytic properties, and reactivity of HCbl were explored to determine the preferred oxidation state as well as its potential role in the formation of the photoproduct in CarH. Natural bond orbital (NBO) analysis was performed to determine the oxidation state of Co in isolated HCbl. Based on the NBO analysis of HCbl, Co clearly had excess negative charge, which is in stark contrast to other alkylCbls where the Co ion is marked by significant positive charge. In sum, NBO results indicate that the CoH bond is strongly polarized and almost ionic. It can be described as protonated Co(I). In addition, DFT was used to explore the bond dissociation energy of HCbl based on homolytic cleavage of the CoH bond. TD-DFT calculations were used to compare computed electronic transitions to the experimentally determined absorption spectrum. The photoreaction of CarH was explored using an isolated model system and a pathway for hydrogen transfer was found. Finally, quantum mechanics/molecular mechanics (QM/MM) calculations were employed to investigate the formation of HCbl in CarH.

Free Energy Landscape and Proton Transfer Pathways of the Transimination Reaction at the Active site of the Serine Hydroxymethyltransferase Enzyme in Aqueous Medium.

Serine hydroxymethyltransferase (SHMT) is a ubiquitous enzyme belonging to the fold type I or aspartate aminotransferase (AspAT) family of the pyridoxal 5'-phosphate (PLP)-dependent enzymes. Like other PLP-dependent enzymes, SHMT also undergoes the so-called transimination reaction before exhibiting its enzymatic activity. The transimination process constitutes an important pre-step for all PLP-dependent enzymes, where an internal aldimine of the PLP-enzyme complex gets converted to an external aldimine of the substrate-PLP complex at the active site of the enzyme. In case of the transimination reaction involving SHMT, the PLP molecule bound to the active site lysine residue of SHMT (internal aldimine) gets detached from the enzyme by a serine substrate to produce an external aldimine complex, where the PLP is now bound to the serine substrate. In the current study, the free energy surfaces and reaction pathways of different steps of the transimination reaction at the active site of SHMT are investigated by employing hybrid quantum mechanical/molecular mechanical (QM/MM) simulations combined with metadynamics methods of rare event sampling. It is found that the process of transimination involving serine and PLP at the active site of the SHMT enzyme takes place through different elementary steps such as the formation of the first geminal diamine intermediate (GDI1), transfer of a proton from the substrate serine to the phenolic oxygen of PLP, followed by another proton transfer from PLP to the amine nitrogen of lysine with the formation of the second geminal diamine intermediate (GDI2), and finally, detachment of the active site lysine residue from PLP to produce the external aldimine.

Multispectroscopic and molecular modeling strategy to explore the interaction of cholest-5-en-7-one with human serum albumin: DFT and Hirshfeld surface analysis

The present study accounts for cholest-5-en-7-one (steroid) synthesis using selenium dioxide and silica as well as its identification using high-resolution mass spectrometry (HRMS), FT-IR, NMR, and elemental analysis. Density functional theory (DFT) calculations were used to optimize the steroid's geometry, which was then compared to single-crystal X-ray diffraction data, indicating that the computational and experimental results were in good agreement. UV–vis absorption titration, fluorescence spectral methods, circular dichroism (CD), and dynamic light scattering (DLS)were used to investigate the well-identified steroid's in vitro molecular interaction with human serum albumin (HSA).The results and binding parameter indicate that the steroid has significant binding affinity for HSA. Molecular docking was performed and found that the steroid can interact with the hydrophobic cavity of HSA through hydrogen and hydrophobic contacts. Molecular dynamics simulation was used to confirm the stability of the HSA-steroid complex. Combined quantum mechanics-molecular mechanics (QM-MM) methods were applied to know binding energy of system and individual components for atomic level interactions indicating a significant interaction between the steroid and the biomacromolecules. The findings presented here contribute to a better understanding of steroid pharmacodynamics.

Structural Dynamics and Catalytic Mechanism of ATP13A2 (PARK9) from Simulations.

ATP13A2 is a gene encoding a protein of the P5B subfamily of ATPases and is a PARK gene. Molecular defects of the gene are mainly associated with variations of Parkinson's disease (PD). Despite the established importance of the protein in regulating neuronal integrity, the three-dimensional structure of the protein currently remains unresolved crystallographically. We have modeled the structure and reactivity of the full-length protein in its E1-ATP state. Using molecular dynamics (MD), quantum cluster, and quantum mechanical/molecular mechanical (QM/MM) methods, we aimed at describing the main catalytic reaction, leading to the phosphorylation of Asp513. Our MD simulations suggest that two positively charged Mg2+ cations are present at the active site during the catalytic reaction, stabilizing a specific triphosphate binding mode. Using QM/MM calculations, we subsequently calculated the reaction profiles for the phosphoryl transfer step in the presence of one and two Mg2+ cations. The calculated barrier heights in both cases are found to be ∼12.5 and 7.5 kcal mol-1, respectively. We elucidated details of the catalytically competent ATP conformation and the binding mode of the second Mg2+ cofactor. We also examined the role of the conserved Arg686 and Lys859 catalytic residues. We observed that by significantly lowering the barrier height of the ATP cleavage reaction, Arg686 had major effect on the reaction. The removal of Arg686 increased the barrier height for the ATP cleavage by more than 5.0 kcal mol-1 while the removal of key electrostatic interactions created by Lys859 to the γ-phosphate and Asp513 destabilizes the reactant state. When missense mutations occur in close proximity to an active site residue, they can interfere with the barrier height of the reaction, which can halt the normal enzymatic rate of the protein. We also found large binding pockets in the full-length structure, including a transmembrane domain pocket, which is likely where the ATP13A2 cargo binds.

Origins of Acid-Gas Stability Behavior in Zeolitic Imidazolate Frameworks: The Unique High Stability of ZIF-71

Zeolitic imidazolate frameworks (ZIFs) are promising materials for industrial process separations, but recent literature reports have highlighted their vulnerability to acid gases (e.g., SO2, CO2, NO2, H2S), often present in practical applications. While previous work has documented the widely varying stability behavior of many ZIFs under varying (humid and dry) acid gas environments, efforts to explain or correlate these experimental observations via empirical descriptors have not succeeded. A key observation is that ZIF-71 (RHO topology) is an extraordinarily stable ZIF material, retaining both structure and porosity under prolonged humid SO2 exposure whereas many other well-known ZIFs with different linkers and topologies (such as ZIF-8) were shown to degrade. Through a combination of hybrid quantum mechanics/molecular mechanics (QM/MM) based methods and statistical mechanical models, we successfully explain this important experimental observation via atomistic investigations of the reaction mechanism. Our holistic approach reveals an ∼9 times lower average defect formation rate in ZIF-71 RHO compared to ZIF-8 SOD, leading to the conclusion that the observed experimental stability of this material rises from kinetic effects. Moreover, our analysis reveals that differing stability of the two materials is determined by the distributions of acid gas molecules, which is difficult to capture using empirical descriptors. Our results suggest wider applicability of the present approach, toward identifying tuned functional groups and topologies that move the acid gas distributions away from more reactive sites and thus allow enhanced kinetic stability.

Hydrolysis Mechanism of the Linkers by Matrix Metalloproteinase-9 Using QM/MM Calculations.

Activatable cell-penetrating peptides (ACPPs) are known to be able to decrease the cytotoxicity of cell-penetrating peptide (CPP)-based drug delivery systems. Furthermore, they can improve the targeting of CPPs when specifically recognized and hydrolyzed by characteristic proteases. A comprehensive and profound understanding of the recognition and hydrolysis process will provide a better design of the ACPP-based drug delivery system. Previous studies have clearly described how ACPPs are recognized and bound by MMPs. However, the hydrolysis mechanism of ACPPs is still unsolved. This work focuses on a proteinase-sensitive cleavable linker of ACPPs (PLGLAG), the key structure for recognition and hydrolysis, trying to determine the mechanism by which MMP-9 hydrolyzes its substrate PLGLAG. The quantum mechanics/molecular mechanics (QM/MM) calculations herein show that MMP-9 proteolysis is a water-mediated four-step reaction. More specifically, it consists of (i) nucleophilic attack, (ii) hydrogen-bond rearrangement, (iii) proton transfer, and finally (iv) amide bond rupture. Considering the reversibility of multistep reaction, the second step (i.e., hydrogen-bond rearrangement) has the highest barrier and is the rate-limiting step in the hydrolysis of PLGLAG. The possible design and improvement of the key P1 and P1' sites are also explored through mutations. The present results indicate that, while the mutations affect the reaction energy barriers and the rate-limiting steps, all mutants considered could be hydrolyzed by MMP-9. To provide further insights, the hydrolysis mechanism of MMP-2, which has a similar hydrolysis process to that of MMP-9 but with different reaction barriers, is also studied and compared. As a result, this work provides detailed insights into the hydrolysis mechanism of ACPPs by MMP-9 and, thus, also possible insights for the development of new strategies for ACPP-based delivery systems.

Development of Range-Corrected Deep Learning Potentials for Fast, Accurate Quantum Mechanical/Molecular Mechanical Simulations of Chemical Reactions in Solution.

We develop a new deep potential─range correction (DPRc) machine learning potential for combined quantum mechanical/molecular mechanical (QM/MM) simulations of chemical reactions in the condensed phase. The new range correction enables short-ranged QM/MM interactions to be tuned for higher accuracy, and the correction smoothly vanishes within a specified cutoff. We further develop an active learning procedure for robust neural network training. We test the DPRc model and training procedure against a series of six nonenzymatic phosphoryl transfer reactions in solution that are important in mechanistic studies of RNA-cleaving enzymes. Specifically, we apply DPRc corrections to a base QM model and test its ability to reproduce free-energy profiles generated from a target QM model. We perform these comparisons using the MNDO/d and DFTB2 semiempirical models because they differ in the way they treat orbital orthogonalization and electrostatics and produce free-energy profiles which differ significantly from each other, thereby providing us a rigorous stress test for the DPRc model and training procedure. The comparisons show that accurate reproduction of the free-energy profiles requires correction of the QM/MM interactions out to 6 Å. We further find that the model's initial training benefits from generating data from temperature replica exchange simulations and including high-temperature configurations into the fitting procedure, so the resulting models are trained to properly avoid high-energy regions. A single DPRc model was trained to reproduce four different reactions and yielded good agreement with the free-energy profiles made from the target QM/MM simulations. The DPRc model was further demonstrated to be transferable to 2D free-energy surfaces and 1D free-energy profiles that were not explicitly considered in the training. Examination of the computational performance of the DPRc model showed that it was fairly slow when run on CPUs but was sped up almost 100-fold when using NVIDIA V100 GPUs, resulting in almost negligible overhead. The new DPRc model and training procedure provide a potentially powerful new tool for the creation of next-generation QM/MM potentials for a wide spectrum of free-energy applications ranging from drug discovery to enzyme design.

Crystallography and QM/MM Simulations Identify Preferential Binding of Hydrolyzed Carbapenem and Penem Antibiotics to the L1 Metallo-β-Lactamase in the Imine Form.

Widespread bacterial resistance to carbapenem antibiotics is an increasing global health concern. Resistance has emerged due to carbapenem-hydrolyzing enzymes, including metallo-β-lactamases (MβLs), but despite their prevalence and clinical importance, MβL mechanisms are still not fully understood. Carbapenem hydrolysis by MβLs can yield alternative product tautomers with the potential to access different binding modes. Here, we show that a combined approach employing crystallography and quantum mechanics/molecular mechanics (QM/MM) simulations allow tautomer assignment in MβL:hydrolyzed antibiotic complexes. Molecular simulations also examine (meta)stable species of alternative protonation and tautomeric states, providing mechanistic insights into β-lactam hydrolysis. We report the crystal structure of the hydrolyzed carbapenem ertapenem bound to the L1 MβL from Stenotrophomonas maltophilia and model alternative tautomeric and protonation states of both hydrolyzed ertapenem and faropenem (a related penem antibiotic), which display different binding modes with L1. We show how the structures of both complexed β-lactams are best described as the (2S)-imine tautomer with the carboxylate formed after β-lactam ring cleavage deprotonated. Simulations show that enamine tautomer complexes are significantly less stable (e.g., showing partial loss of interactions with the L1 binuclear zinc center) and not consistent with experimental data. Strong interactions of Tyr32 and one zinc ion (Zn1) with ertapenem prevent a C6 group rotation, explaining the different binding modes of the two β-lactams. Our findings establish the relative stability of different hydrolyzed (carba)penem forms in the L1 active site and identify interactions important to stable complex formation, information that should assist inhibitor design for this important antibiotic resistance determinant.

Novel Molecules derived from 3-O-(6-galloylglucoside) inhibit Main Protease of SARS-CoV 2 In Silico.

The ongoing pandemic caused by the severe acute respiratory syndrome 2 (SARS-CoV 2) has led to more than 168 million confirmed cases with 3.5 million deaths as at 28th May, 2021 across 218 countries. The virus has a cysteine protease called main protease (Mpro) which is significant to it life cycle, tagged as a suitable target for novel antivirals. In this computer-assisted study, we designed 100 novel molecules through an artificial neural network-driven platform called LigDream (https://playmolecule.org/LigDream/) using 3-O-(6-galloylglucoside) as parent molecule for design. Druglikeness screening of the molecules through five (5) different rules was carried out, followed by a virtual screening of those molecules without a single violation of the druglike rules using AutoDock Vina against Mpro. The in silico pharmacokinetic features were predicted and finally, quantum mechanics/molecular mechanics (QM/MM) study was carried out using Molecular Orbital Package 2016 (MOPAC2016) on the overall hit compound with controls to determine the stability and reactivity of the lead molecule. The findings showed that eight (8) novel molecules violated none of the druglikeness rules of which three (3) novel molecules (C33, C35 and C54) showed the utmost binding affinity of −8.3 kcal/mol against Mpro; C33 showed a good in silico pharmacokinetic features with acceptable level of stability and reactively better than our controls based on the quantum chemical descriptors analysis. However, there is an urgent need to carry out more research on these novel molecules for the fight against the disease.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11696-021-01899-y.

Modeling Spectral Tuning in Red Fluorescent Proteins Using the Dipole Moment Variation upon Excitation.

We describe a model for spectral tuning in red fluorescent proteins (RFPs) based on the relation between an electronic structure descriptor, the dipole moment variation upon excitation (DMV), and the excitation energy of a protein. This approach aims to overcome the problem of accurate prediction of excitation energies in RFPs, which span a very narrow window of band maxima. The latter roughly corresponds to the energy range of 0.1 eV, which is comparable with typical errors in calculations of the excitation energy by conventional quantum chemistry methods. In this work, we demonstrate a strong quantitative correlation between DMV values, obtained computationally with modest efforts, and excitation energies ΔEex at the experimental excitation band maxima for a series of RFPs with bands between 570 and 605 nm. Protein models are constructed by motifs of the relevant crystal structures, and atomic coordinates are optimized in quantum mechanics/molecular mechanics (QM/MM) calculations with QM-subsystems composed of large chromophore-containing regions. DMV values are evaluated with the electron density computed at the time-dependent density functional theory (TDDFT) level using several functionals and basis sets. We show that the results obtained with the CAM-B3LYP, BHHLYP, and M06-2X functionals demonstrate favorable correlations between DMV and ΔEex with the mean absolute error less than 0.01 eV. Taking into account the solid theoretical grounds of the relation between the DMV and the excitation energy in fluorescent proteins, the described modeling strategy presents a rational tool for spectral tuning in these efficient markers for in vivo imaging.

Bridging Carotenoid-to-Bacteriochlorophyll Energy Transfer of Purple Bacteria LH2 With Temperature Variations: Insights From Conformational Changes.

Photosynthesis is a key process for converting light energy into chemical energy and providing food for lives on Earth. Understanding the mechanism for the energy transfers could provide insights into regulating energy transfers in photosynthesis and designing artificial photosynthesis systems. Many efforts have been devoted to exploring the mechanism of temperature variations affecting the excitonic properties of LH2. In this study, we performed all-atom molecular dynamics (MD) simulations and quantum mechanics calculations for LH2 complex from purple bacteria along with its membrane environment under three typical temperatures: 270, 300, and 330 K. The structural analysis from validated MD simulations showed that the higher temperature impaired interactions at N-terminus of both α and β polypeptide helices and led to the dissociation of this hetero polypeptide dimer. Rhodopin-β-D-glucosides (RG1) moved centripetally with α polypeptide helices when temperature increased and enlarged their distances with bacteriochlorophylls molecules that have the absorption peak at 850 nm (B850), which resulted in reducing the coupling strengths between RG1 and B850 molecules. The present study reported a cascading mechanism for temperature regulating the energy transfers in LH2 of purple bacteria.

Multiscale Modeling of Electronic Spectra Including Nuclear Quantum Effects.

Theoretical prediction of electronic absorption spectra without input from experiments is no easy feat, as it requires addressing all of the factors that affect line shapes. In practice, however, the methodologies are limited to treat these ingredients only to a certain extent. Here, we present a multiscale protocol that addresses the temperature, solvent, and nuclear quantum effects as well as anharmonicity and the reconstruction of the final spectra from individual transitions. First, quantum mechanics/molecular mechanics (QM/MM) molecular dynamics is conducted to obtain trajectories of solute–solvent configurations, from which the corresponding quantum-corrected ensembles are generated through the generalized smoothed trajectory analysis (GSTA). The optical spectra of the ensembles are then produced by calculating vertical transitions using time-dependent density-functional theory (TDDFT) with implicit solvation. To obtain the final spectral shapes, the stick spectra from TDDFT are convoluted with Gaussian kernels where the half-widths are determined by a statistically motivated strategy. We have tested our method by calculating the UV–vis spectra of a recently discovered acridine photocatalyst in two redox states. Vibronic progressions and broadenings due to the finite lifetime of the excited states are not included in the methodology yet. Nuclear quantization affects the relative peak intensities and widths, which is necessary to reproduce the experimental spectrum. We have also found that using only the optimized geometry of each molecule works surprisingly well if a proper empirical broadening factor is applied. This is explained by the rigidity of the conjugated chromophore moieties of the selected molecules, which are mainly responsible for the excitations in the spectra. In contrast, we have also shown that other parts of the molecules are flexible enough to feature anharmonicities that impair the use of other techniques such as Wigner sampling.

O to bR transition in bacteriorhodopsin occurs through a proton hole mechanism

Extensive classical and quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations are used to establish the structural features of the O state in bacteriorhodopsin (bR) and its conversion back to the bR ground state. The computed free energy surface is consistent with available experimental data for the kinetics and thermodynamics of the O to bR transition. The simulation results highlight the importance of the proton release group (PRG, consisting of Glu194/204) and the conserved arginine 82 in modulating the hydration level of the protein cavity. In particular, in the O state, deprotonation of the PRG and downward rotation of Arg82 lead to elevated hydration level and a continuous water network that connects the PRG to the protonated Asp85. Proton exchange through this water network is shown by ∼0.1-μs semiempirical QM/MM free energy simulations to occur through the generation and propagation of a proton hole, which is relayed by Asp212 and stabilized by Arg82. This mechanism provides an explanation for the observation that the D85S mutant of bacteriorhodopsin pumps chloride ions. The electrostatics-hydration coupling mechanism and the involvement of all titration states of water are likely applicable to many biomolecules involved in bioenergetic transduction.

Rational Redesign of Enzyme via the Combination of Quantum Mechanics/Molecular Mechanics, Molecular Dynamics, and Structural Biology Study.

Increasing demands for efficient and versatile chemical reactions have prompted innovations in enzyme engineering. A major challenge in engineering α-ketoglutarate-dependent oxygenases is to develop a rational strategy which can be widely used for directly evolving the desired mutant to generate new products. Herein, we report a strategy for rational redesign of a model enzyme, 4-hydroxyphenylpyruvate dioxygenase (HPPD), based on quantum mechanics/molecular mechanics (QM/MM) calculation and molecular dynamic simulations. This strategy enriched our understanding of the HPPD catalytic reaction pathway and led to the discovery of a series of HPPD mutants producing hydroxyphenylacetate (HPA) as the alternative product other than the native product homogentisate. The predicted HPPD-Fe(IV)═O-HPA intermediate was further confirmed by the crystal structure of Arabidopsis thaliana HPPD/S267W complexed with HPA. These findings not only provide a good understanding of the structure-function relationship of HPPD but also demonstrate a generally applicable platform for the development of biocatalysts.

H2O-Bridged Proton-Transfer Channel in Emitter Species Formation in Obelin Bioluminescence.

Bioluminescence of a number of marine organisms is conditioned by Ca2+-regulated photoprotein (CaRP) with coelenterazine as the reaction substrate. The reaction product, coelenteramide, at the first singlet excited state (S1) is the emitter of CaRP. The S1-state coelenteramide is produced via the decomposition of coelenterazine dioxetanone. Experiments suggested that the neutral S1-coelenteramide is the primary emitter species. This supposition contradicts with theoretical calculations showing that the anionic S1-coelenteramide is a primary product of the decomposition of coelenterazine dioxetanone. In this study, applying molecular dynamic (MD) simulations and the hybrid quantum mechanics/molecular mechanics (QM/MM) method, we investigated a proton-transfer (PT) process taking place in CaRP obelin from Obelia longissima for emitter formation. Our calculations demonstrate a concerted PT process with a water molecule as a bridge between anionic S1-coelenteramide and the nearest histidine residue. The low activation barrier as well as the strong hydrogen-bond network between the proton donor and the proton acceptor suggests a fast PT process comparable with that of the lifetime of excited anionic S1-coelenteramide. The existence of the PT process eliminates the discrepancy between experimental and theoretical studies. The fast PT process at emitter formation can also take place in other CaRPs.

Challenges for the theoretical description of the mechanism and kinetics of reactions catalyzed by zeolites

Zeolites are widely used as catalysts for the processing of petroleum to produce transportation fuels, the synthesis of a wide variety of chemicals, and for the abatement of automotive emissions. These applications have stimulated an interest in describing the mechanism and kinetics for zeolite-catalyzed reactions using theoretical methods. This Mini-review summarizes the author’s efforts towards this goal. It is shown that accurate predictions of adsorption and activation enthalpies and entropies requires that several criteria be met. The first is a correct description of the structure of the catalytically active center, as well as the portion of the zeolite framework immediately surrounding the active center and that located far from the active center. Second, the level of density functional theory (DFT) must be sufficiently high to account for the effects of dispersive interactions between the adsorbate, the active center, and the immediately surrounding zeolite atoms. Third, dispersive and coulombic interactions between the atoms in the vicinity of the active center and the balance of the zeolite framework must also be accounted for. It is shown that these conditions can be met using hybrid quantum mechanics/molecular mechanics (QM/MM) together with a high-level exchange-correlation functional and a large basis set. The success of our QM/MM approach is illustrated for reactions of light alkanes in H-MFI, as well as other protonated zeolites, and in Ga/H-MFI. We show that for low temperatures (<400 K), the QM/MM approach gives good predictions of molecular adsorption enthalpies and activation enthalpies for elementary reactions. This is also true for higher temperatures (>400 K) if the effects of configuration are considered using a correction obtained from configurationally biased Monte Carlo (CBMC) calculations. Calculations of the molecular adsorption entropy and the activation entropy for elementary reactions are more difficult to predict accurately. Application of the quasi-rigid rotor harmonic approximation overpredicts the loss of entropy of adsorption from the gas phase, particularly for zeolites containing large cavities and channels. CBMC corrections capture this deviation well for molecular adsorption and for early transition states resembling the adsorbed state but are inadequate for late transition states involving two loosely associated fragments.

Theoretical Insight Into the Ultralong Room-Temperature Phosphorescence of Nonplanar Aromatic Hydrocarbon.

Purely aromatic hydrocarbon materials with ultralong room-temperature phosphorescence (RTP) were reported recently, but which is universally recognized as unobservable. To reveal the inherent luminescent mechanism, two compounds, i.e., PT with a faint RTP and HD with strong RTP featured by nonplanar geometry, were chosen as a prototype to study their excited-state electronic structures by using quantum mechanics/molecular mechanics (QM/MM) model. It is demonstrated that the nonplanar ethylene brides can offer σ-electron to strengthen spin-orbit coupling (SOC) between singlet and triplet excited states, which can not only promote intersystem crossing (ISC) of S1→Tn to increase the population of triplet excitons, but also accelerate the radiative decay rate of T1→S0, and thus improving RTP. Impressively, the nonradiative decay rate only has a small increase, owing to the synergistic effect between the increase of SOC and the reduction of reorganization energy of T1→S0 caused by the restricted torsional motions of aromatic rings. Therefore, a bright and long-lived RTP was obtained in aromatic hydrocarbon materials with twisted structure. This work provided a new insight into the ultralong RTP in pure organic materials.

Unrevealing the Proteolytic Activity of RgpB Gingipain from Computational Simulations.

Alzheimer's disease represents one of the greatest medical concerns for today's population and health services. Its multifactorial inherent nature represents a challenge for its treatment and requires the development of a broad spectrum of drugs. Recently, the cysteine protease gingipain RgpB has been related to neurodegenerative diseases, including Alzheimer's disease, and its inhibition appears to be a promising neuroprotective strategy. Given these features, a computational study that integrates molecular dynamics (MD) simulations with classical and hybrid quantum mechanics/molecular mechanics (QM/MM) potentials was carried out to unravel the atomistic details of RgpB activity. First, a preliminary study based on principal component analysis (PCA), determined the protonation state of the Cys/His catalytic dyad, as well as the crucial role of a flexible loop that favors reactive interactions of the catalytic residues and the peptide in the precatalytic state in its closed conformation. Then, different mechanisms were explored by means of QM/MM MD simulations. The most favorable mechanism consists of two stages. First is an acylation stage that takes place in two steps where, initially, the sulfur atom of the C244 residue attacks the carbonylic carbon of the peptide and the proton of the C244 residue is transferred to the amino group of the peptide in a concerted manner. Subsequently, the peptide bond is broken, and a fragment of the peptide is released. After that, the deacylation stage takes place in a single step where a water molecule attacks the carbonylic carbon of the peptide and a proton of the water is transferred to the C244 residue. The free energy barrier of the rate limiting step is in very good agreement with available experimental data. The mechanism exhibits an unusual role of H211 residue compared with other cysteine proteases but a crucial role of the peptide in triggering the catalysis. Notably, the atomic and energetic particularities found represent a significant contribution to the comprehension of the reaction mechanism and a great opportunity for the design of efficient inhibitors of gingipain RgpB.

Structural Origin and Vibrational Fingerprints of the Ultrafast Excited State Proton Transfer of the Pyranine-Acetate Complex in Aqueous Solution.

The excited state proton transfer (ESPT) reaction from the photoacid 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS or pyranine) to an acetate molecule has been investigated in explicit aqueous solution via excited state ab initio molecular dynamics simulations based on hybrid quantum/molecular mechanics (QM/MM) potentials. In all the trajectories, the direct proton transfer has been observed in the excited state within 1 ps. We find that the initial structural configuration extracted from the ground state distribution strongly affects the ESPT kinetics. Indeed, the relative orientation of the proton donor-acceptor pair and the presence of a water molecule hydrogen bonded to the phenolic acid group of the pyranine are the key factors to facilitate the ESPT. Furthermore, we analyze the vibrational fingerprints of the ESPT reaction, reproducing the blue shift of the acetate CO stretching (COac), from 1666 to 1763 cm-1 testifying the transformation of acetate to acetic acid. Finally, our findings suggest that the acetate CC stretching (CCac) is also sensitive to the progress of the ESPT reaction. The CCac stretching is indeed ruled by the two vibrational modes (928 and 1426 cm-1), that in the excited state are alternately activated when the proton is shared or bound to the donor/acceptor, respectively.

Using Constrained Density Functional Theory to Track Proton Transfers and to Sample Their Associated Free Energy Surface.

Ab initio molecular dynamics (AIMD) and quantum mechanics/molecular mechanics (QM/MM) methods are powerful tools for studying proton solvation, transfer, and transport processes in various environments. However, due to the high computational cost of such methods, achieving sufficient sampling of rare events involving excess proton motion—especially when Grotthuss proton shuttling is involved—usually requires enhanced free energy sampling methods to obtain informative results. Moreover, an appropriate collective variable (CV) that describes the effective position of the net positive charge defect associated with an excess proton is essential both for tracking the trajectory of the defect and for the free energy sampling of the processes associated with the resulting proton transfer and transport. In this work, such a CV is derived from first principles using constrained density functional theory (CDFT). This CV is applicable to a broad array of proton transport and transfer processes as studied via AIMD and QM/MM simulations.