Molecular Mechanics Calculations Research Articles

STORMM: Structure and topology replica molecular mechanics for chemical simulations.

The Structure and TOpology Replica Molecular Mechanics (STORMM) code is a next-generation molecular simulation engine and associated libraries optimized for performance on fast, vectorized central processor units and graphics processing units (GPUs) with independent memory and tens of thousands of threads. STORMM is built to run thousands of independent molecular mechanical calculations on a single GPU with novel implementations that tune numerical precision, mathematical operations, and scarce on-chip memory resources to optimize throughput. The libraries are built around accessible classes with detailed documentation, supporting fine-grained parallelism and algorithm development as well as copying or swapping groups of systems on and off of the GPU. A primary intention of the STORMM libraries is to provide developers of atomic simulation methods with access to a high-performance molecular mechanics engine with extensive facilities to prototype and develop bespoke tools aimed toward drug discovery applications. In its present state, STORMM delivers molecular dynamics simulations of small molecules and small proteins in implicit solvent with tens to hundreds of times the throughput of conventional codes. The engineering paradigm transforms two of the most memory bandwidth-intensive aspects of condensed-phase dynamics, particle-mesh mapping, and valence interactions, into compute-bound problems for several times the scalability of existing programs. Numerical methods for compressing and streamlining the information present in stored coordinates and lookup tables are also presented, delivering improved accuracy over methods implemented in other molecular dynamics engines. The open-source code is released under the MIT license.

Deciphering the shape selective conformational equilibrium of E- and Z-locked azobenzene-tetraethylammonium ion in regulating photo-switchable K+-ion channel blocking.

The search for photo-switchable optopharmacological agents that can block ion channels has been a prevalent area owing to its prime advantages of reversibility and specificity over the traditional blockers. However, the quest for a higher blocking ability shown by a less stable photo-isomer to perfectly suit the requirement of the optopharmacological agents is still ongoing. To date, only a marginal improvement in terms of blocking ability is observed by the less stable E-isomer of para-substituted locked azobenzene with TEA (LAB-TEA) for the K+-ion channel. Thus, rationalization of the limitation for achieving high activity by the E-isomer is rather essential to aid the improvement of the efficiency of photoswitchable blocker drugs. Herein, we report a molecular-level analysis on the mechanism of blocking by E- and Z-LAB-TEA with the bacterial KcsA K+-ion channel using Molecular Dynamics (MD) simulation and Quantum Mechanical (QM) calculations. The positively charged TEA fragment engages in stronger electrostatic interactions, while the neutral LAB fragment engages in weaker dispersive interactions. The binding free energy calculated by Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) for E-LAB-TEA (-22.3 kcal mol-1) shows less thermodynamic preference for binding with K+-ion channels than Z-LAB-TEA (-21.6 kcal mol-1) corroborating the experimental observation. The correlation between the structure and the binding ability of E- and Z-isomers of LAB-TEA indicates that the channel gate is narrow and acts as a bottleneck for the entry of the binder molecule inside the large cavity. Upon irradiation, the Z-isomer converts into a less stable but long and planar E-isomer (ΔE of photoisomerism = 7.0 kcal mol-1, at SA2-CASPT2(6,4)/6-31+G(d)//CASSCF(6,4)/6-31+G(d)), which is structurally more suitable to fit into the narrow channel gate rather than the curved and non-planar Z-LAB-TEA. Thus, a reduction in the ionic current is observed owing to the preferential entry and subsequent blocking by E-LAB-TEA. Discontinuing the irradiation leads to conversion to the Z-isomer, the curved nature of which hinders its spontaneous release outside the cavity, thereby contributing only a small increase in the ionic current.

Effect of external electric field on copper/silica contact electrification and adhesion: insight from first-principles and molecular mechanics investigations

The electrostatic force induced by charge transfer during contact electrification is one of the main components of adhesion force at the solid interface. Some studies found that the magnitude of charge transfer and the consequently electrostatic force can be tuned by the external electric field. However, the detailed mechanism is still lacking in understanding. In this study, the effect of external electric field on copper/silica contact electrification and adhesion is studied via first-principles and molecular mechanics calculations and the mechanism is revealed by electrostatic potential and adhesion energy analysis. It is proved that the external electric field can affect the contact potential difference, which is the driving force of contact electrification, thus influencing the magnitude of charge transfer and electrostatic force. When the electric field direction is the same as the electron transfer direction, the contact electrification can be suppressed, leading to the decrease in the ratio of electrostatic force to van der Waals force. In particularly, the contact electrification and electrostatic force can be completely eliminated when applying a specific electric field intensity. This can provide an inspiration for quantitatively studying the source of adhesion force at solid interface.

Molecular Docking and ADMET Studies to Investigate Antioxidant Potency of New Amides of Piper retrofractum Vahl by Targeting Keap1 Inhibitor

Abstract Antioxidants are considered important in maintaining the balance of free radicals in the body due to exposure to air pollution. Piper retrofractum Vahl which is a traditional Indonesian medicinal herb which is said to have the characteristics of being an antioxidant in preventing free radicals in the body. Therefore, this research aims to investigate possible interactions between new amides of Piper retrofractum Vahl. and Keap1, one of the key proteins of the Keap1/Nrf2 pathway, the major system involved in redox regulation. Molecular docking study, using molecular mechanic calculations with Yasara to investigate binding energy and pkCSM to predict ADMET. Results this study showed that dipiperamides F has binding energy of 9.855 kcal/mol (closest to that of the crystallographic ligands), dipiperamides G (9.543 kcal/mol), piperodione (8.448 kcal/mol), (E)-N-cinnamoyl-2-methoxypiperidine (7.560 kcal/mol), (2E, 12E)-pipertride cadienamid (7.084 kcal/mol), N-isobutyl-(2E, 4E, 10Z)-hexadeca-2, 4, 10-trienamide (6.788 kcal/mol), (R)-1-(2-oxopyrrolidin-3-yl)-5, 6-dihydropyridin-2(1H)-one (6.524 kcal/mol), 2E, 14Z)-N-isobutyleicosa-2, 14-dienamide (5.116 kcal/mol). Visualization of receptors-ligands complex showed data on hydrogen bonds and no-covalen interactions, including hydrogen bond distances. Finally, ADMET (Adsorption, Desorption, Metabolism, Excretion, Toxicity) predictions and drug-likeness properties were performed on the tested compound. Our study indicates that new amides from Piper retrofractum Vahl may behave as potential natural antioxidant agents by targeting the Keap1 inhibitor.

Analysis of the interaction of antimalarial agents with Plasmodium falciparum glutathione reductase through molecular mechanical calculations.

Malaria remains a significant global health challenge with emerging resistance to current treatments. Plasmodium falciparum glutathione reductase (PfGR) plays a critical role in the defense mechanisms of malaria parasites against oxidative stress. In this study, we investigate the potential of targeting PfGR with conventional antimalarials and dual drugs combining aminoquinoline derivatives with GR inhibitors, which reveal promising interactions between PfGR and studied drugs. The naphthoquinone Atovaquone demonstrated particularly high affinity and potential dual-mode binding with the enzyme active site and cavity. Furthermore, dual drugs exhibit enhanced binding affinity, suggesting their efficacy in inhibiting PfGR, where the aliphatic ester bond (linker) is essential for effective binding with the enzyme's active site. Overall, this research provides important insights into the interactions between antimalarial agents and PfGR and encourages further exploration of its role in the mechanisms of action of antimalarials, including dual drugs, to enhance antiparasitic efficacy. The drugs were tested as PfGR potential inhibitors via molecular docking on AutoDock 4, which was performed based on the preoptimized structures in HF/3-21G-PCM level of theory on ORCA 5. Drug-receptor systems with the most promising binding affinities were then studied with a molecular dynamic's simulation on AMBER 16. The molecular dynamics simulations were performed with a 100ns NPT ensemble employing GAFF2 forcefield in the temperature of 310K, integration time step of 2fs, and non-bond cutoff distance of 6.0Å.

Development of Inhibitory Compounds for Metallo-beta-lactamase through Computational Design and Crystallographic Analysis.

Metallo-β-lactamases (MBL) deactivate β-lactam antibiotics through a catalytic reaction caused by two zinc ions at the active center. Since MBLs deteriorate a wide range of antibiotics, they are dangerous factors for bacterial multidrug resistance. In this work, organic synthesis, computational design, and crystal structure analysis were performed to obtain potent MBL inhibitors based on a previously identified hit compound. The hit compound comprised 3,4-dihydro-2(1H)-quinolinone linked with a phenyl-ether-methyl group via a thiazole ring. In the first step, the thiazole ring was replaced with a tertiary amine to avoid the planar structure. In the second step, we virtually modified the compound by keeping the quinolinone backbone. Every modified compound was bound to a kind of MBL, imipenemase-1 (IMP-1), and the binding pose was optimized by a molecular mechanics calculation. The binding scores were evaluated for the respective optimized binding poses. Given the predicted binding poses and calculated binding scores, candidate compounds were determined for organic syntheses. The inhibitory activities of the synthesized compounds were measured by an in vitro assay for two kinds of MBLs, IMP-1 and New Delhi metallo-β-lactamase (NDM-1). A quinolinone connected with an amine bound with methyl-phenyl-ether-propyl and cyclohexyl-ethyl showed a 50% inhibitory concentration of 4.8 μM. An X-ray crystal analysis clarified the binding structure of a synthesized compound to IMP-1. The δ-lactam ring of quinolinone was hydrolyzed, and the generated carboxyl group was coordinated with zinc ions. The findings on the chemical structure and binding pose are expected to be a base for developing MBL inhibitors.

FFParam-v2.0: A Comprehensive Tool for CHARMM Additive and Drude Polarizable Force-Field Parameter Optimization and Validation.

Developing production quality CHARMM force-field (FF) parameters is a very detailed process involving a variety of calculations, many of which are specific for the molecule of interest. The first version of FFParam was developed as a standalone Python package designed for the optimization of electrostatic and bonded parameters of the CHARMM additive and polarizable Drude FFs by using quantum mechanical (QM) target data. The new version of FFParam has multiple new capabilities for FF parameter optimization and validation, with an emphasis on the ability to use condensed-phase target data in optimization. FFParam-v2 allows optimization of Lennard-Jones (LJ) parameters using potential energy scans of interactions between selected atoms in a molecule and noble gases, viz., He and Ne, and through condensed-phase calculations, from which experimental observables such as heats of vaporization and free energies of solvation may be obtained. This functionality serves as a gold standard for both optimizing parameters and validating the performance of the final parameters. A new bonded parameter optimization algorithm has been introduced to account for simultaneously optimizing multiple molecules sharing parameters. FFParam-v2 also supports the comparison of normal modes and the potential energy distribution of internal coordinates towards each normal mode obtained from QM and molecular mechanics calculations. Such comparison capability is vital to validate the balance among various bonded parameters that contribute to the complex normal modes of molecules. User interaction has been extended beyond the original graphical user interface to include command-line interface capabilities that allow for integration of FFParam in workflows, thereby facilitating the automation of parameter optimization. With these new functionalities, FFParam is a more comprehensive parameter optimization tool for both beginners and advanced users.

Toward Greater DNA Stability by Leveraging the Proton-Donating Ability of Protic Ionic Liquids.

Deoxyribonucleic acid (DNA) stability is a prerequisite in many applications, ranging from DNA-based vaccines and data storage to gene therapy. However, the strategies to enhance DNA stability are limited, and the underlying mechanisms are poorly understood. Ionic liquids (ILs), molten salts of organic cations and organic/inorganic anions, are showing tremendous prospects in myriads of applications. With a judicious choice of constituent ions, the protic nature of ILs can be tuned. In this work, we investigate the relative stability of full-length genomic DNA in aqueous IL solutions of increasing protic nature. Our experimental measurements show that the protic ionic liquids (PILs) enhance the DNA melting temperature significantly while unaltering its native B-conformation. Molecular dynamics simulations and quantum mechanical calculation results suggest that the intramolecular Watson-Crick H-bonding in DNA remains unaffected and, in addition, the PILs induce stronger H-bonding networks in solution through their ability to make multiple intermolecular H-bonds with the nucleobases and among its constituent ions, thus aiding greater DNA stability. The detailed understanding obtained from this study could bring about the much-awaited breakthrough in improved DNA stability for its sustained use in the aforesaid applications!

Cysteamine Chemisorption at Mercury-Solution Interfaces in the Context of Redox and Microdissociation Equilibria.

The redox behavior and chemisorption of cysteamine (CA) at a charged mercury surface are described, with an emphasis on its acid-base properties supported by molecular dynamics and quantum mechanical calculations. It was found that CA forms chemisorbed layers on the surface of the mercury electrode. The formation of Hg-CA complexes is connected to mercury disproportionation, as reflected in peaks SII and SI at potentials higher than the electrode potential of zero charge (p.z.c.). Both the process of chemisorption of CA and its consequent redox transformation are proton-dependent. Also, depending on the protonation of CA, the formation of typical populations of chemisorbed conformers can be observed. In addition, cystamine (CA disulfide dimer) can be reduced on the mercury surface. Between the potentials of this reduction and peak SI, the p.z.c. of the electrode used can be found. Furthermore, CA can serve as an LMW catalyst for hydrogen evolution. The mechanistic insights presented here can be used for follow-up research on CA chemisorption and targeted modification of other metallic surfaces.

Mechanochemical evolution of coal microscopic groups: A new pathway for mechanical forces acting on coal spontaneous combustion

Coal spontaneous combustion (CSC) remains a significant threat to regional ecological environments. As coal mining operations extend deeper into the earth, the increasingly complex mechanical force conditions in deep-seated mines escalate the potential risk of CSC. Mechanical forces such as ground stress and mechanical cutting are traditionally believed to be linked to CSC through the following pathway: mechanical forces act → mechanical energy is input → mechanical crushing and pulverization occur → coal–oxygen contact area increases → CSC accelerates. Noteworthily, these forces do more than just physically break coal; they also trigger a mechanochemical effect (MCE) that alters coal's microscopic chemistry. However, an independent evaluation of its influence on CSC was lacking. This study characterized coal's microscopic chemical group responses to the MCE. It was found that the MCE led to the degradation of aliphatic side chains while enhancing the polycondensation of aromatic ring structures, indicating a synergistic effect. Additionally, an increase in oxygen-containing functional groups, such as alkyl/aryl ethers, suggested enhanced interactions of the coal microscopic groups with oxygen due to mechanical forces. Based on these findings, an MCE-modified coal macromolecular model was developed and molecular quantum mechanical calculations were conducted. The results indicated that the MCE boosted coal macromolecule reactivity, thus facilitating easier activation. These conclusions were validated through modern thermal analysis tests. Finally, this study proposed a new pathway of mechanical forces acting on CSC: mechanical forces act → mechanical energy is input → the MCE occurs → evolutions of the microscopic groups within coal are induced → Activity of coal molecules is enhanced → CSC accelerates.

Study of Interactions of Nucleoside Anticancer Drugs, Capecitabine and Gemcitabine, with SWNT and BNNT using Molecular and Quantum Mechanical Calculations

Abstract: Using single-wall carbon nanotubes (SWCNTs) and boron nitride nanotubes (BNNTs), this study evaluated the interactions between Capecitabine (CAP) and Gemcitabine (GEM). Molecular mechanics and quantum mechanics were used in the analysis. : The interaction between CP and GM with SWCNTs and BNNTs under various solvents was analyzed using the self-consistent reaction field (SCRF) as a model and DFT as the analytical method. Additionally, the effect of temperature on the stability of the molecule interactions during the experiment was examined. The thermodynamic properties of the title compounds were analyzed based on theoretical calculations. It included the calculation of Frontier Molecular Orbitals (FMOs) and Total Density of States (DOS). In addition to studying the ionization potential (I), we also examined the other molecular properties of the structures, such as electrophilicity (ω), electron affinity (A), chemical hardness (η), and electronic chemical potential (μ). To investigate the interaction between CAP and GEM with SWCNTs and BNNTs, molecular mechanics methods (MM) including AMBER, OPLS, CHARMM, and MM+ force fields, were employed. Monte Carlo simulation techniques were used to calculate the results at different temperatures. : The effects of the liquid phase and mixed solvent media with varying dielectric constants (Water, DMSO, Methanol, and Ethanol) on the interaction between CAP and GEM using the force fields described above were examined in this study. The correlation between data generated by Monte Carlo, Quantum Mechanics, and Molecular Mechanics was demonstrated. There was a striking similarity in the thermodynamic properties and conformer populations of all three materials.

Development and validation of a general-purpose ReaxFF reactive force field for earth material modeling.

ReaxFF reactive force field bridges the gap between nonreactive molecular simulations and quantum mechanical calculations and has been widely applied during the past two decades. However, its application to earth materials, especially those under high T-P conditions relevant to Earth's interior, is still limited due to the lack of available parameters. Here, we present the development and validation of a ReaxFF force field containing several of the most common elements in Earth's crust, i.e., Si/Al/O/H/Na/K. The force field was trained against a large data set obtained from density functional theory (DFT) calculations, including charges, bond/angle distortion curves, equation of states, ion migration energy profiles, and condensation reaction energies. Different coordination environments were considered in the training set. The fitting results showed that the current force field can well reproduce the DFT data (the Pearson correlation coefficient, Rp, is 0.95). We validated the force field on mineral-water interfaces, hydrous melts/supercritical geofluids, and bulk crystals. It was found that the current force field performed excellently in predicting the structural, thermodynamic, and transport properties of various systems (Rp = 0.95). Moreover, possible applications and future development have been discussed. The results obtained in this study suggest that the current force field holds good promise to model a wide range of processes and thus open opportunities to advance the application of ReaxFF in earth material modeling.

Mechanistic Insights into the Bacterial Luciferase-based Bioluminescence Resonance Energy Transfer Luminescence: The Role of Protein Complex Dimer.

Bacterial bioluminescence holds significant potential in the realm of optical imaging due to the inherent advantages of bioluminescence and ease of operation. However, its practical utility is hindered by its low light intensity. The fusion of bacterial luciferase with a highly fluorescent protein has been demonstrated to significantly enhance autonomous luminescence. Nevertheless, the underlying mechanism behind this enhancement remains unclear, and there is a dearth of research investigating the mechanistic aspects of bioluminescence resonance energy transfer (BRET) luminescence, whether it occurs naturally or can be achieved through experimental means. In this study, we investigated the phenomenon of bacterial luciferase-based BRET luminescence employing a range of computational techniques, including structural modeling, molecular docking, molecular dynamics simulations, as well as combined quantum mechanics and molecular mechanics calculations. The theoretical findings suggest that the BRET luminescence occurs through resonance energy transfer between the excited bioluminophore and the ground chromophore within the protein complex dimer. The proposed mechanism of the protein complex dimer offers a microscopic understanding of the intriguing BRET phenomenon and has the potential to inspire further practical applications in the field of optical imaging.

Amphiphilic nanofibrillated cellulose/polyurethane composites with antibacterial, antifouling and self-healing properties for potential catheter applications

This study focuses on enhancing interventional medical devices, specifically catheters, using a novel composite material. Challenges like corrosion and contamination in vivo, often caused by body fluids' pH, bacteria, and proteins, lead to mechanical damage, bacterial colonization, and biofilm formation on devices like catheters. The objective of this study was to prepare a versatile composite (HFs) by designing polyurethanes (HPU) with an ionic chain extender (HIID) and blending them with amphiphilic nanofibrillated cellulose (Am-CNF). The composite leverages dynamic interactions such as hydrogen bonding and electrostatic forces, as evidenced by Molecular Mechanics (MM) calculations. The H4F0.75 composite exhibited exceptional properties: 99 % length recovery post 600 stretching cycles at 100 % strain, rapid self-healing in artificial urine, high bactericidal activity, and excellent cell viability. Moreover, mechanical aging tests and UV–vis spectral analysis confirmed the material's durability and safety. These findings suggest that the HFs composite holds significant promise for improving catheters' performance in medical applications.

Multiscale Study on the Intramolecular C-S Bond Formation Catalyzed by P450 Monooxygenase CxnD Involved in the Biosynthesis of Chuangxinmycin: The Critical Roles of Noncrystal Water Molecule and Conformational Change.

Cytochrome P450 monooxygenase CxnD catalyzes intramolecular C-S bond formation in the biosynthesis of chuangxinmycin, which is representative of the synthesis of sulfur-containing natural heterocyclic compounds. The intramolecular cyclization usually requires the activation of two reaction sites and a large conformational change; thus, illuminating its detailed reaction mechanism remains challengeable. Here, the reaction pathway of CxnD-catalyzed C-S bond formation was clarified by a series of calculations, including Gaussian accelerated molecular dynamics simulations and quantum mechanical-molecular mechanical calculations. Our results revealed that the C-S formation follows a diradical coupling mechanism. CxnD first employs Cpd I to abstract the hydrogen atom from the imino group of the indole ring, and then, the resulted Cpd II further extracts another hydrogen atom from the thiol group of the side chain to afford a diradical intermediate, in which a noncrystal water molecule entering into the active site after the formation of Cpd I was proved to play an indispensable role. Moreover, the diradical intermediate cannot directly perform the coupling reaction. It should first undergo a series of conformational changes leading to the proximity of two reaction sites. It is the flexibility of the active site of the enzyme and the side chain of the substrate that makes the diradical coupling to be successful.

Influence of Ionic Liquids on the Aggregation and Preaggregation Phenomena of Asphaltenes in Model Solvent Mixtures by Molecular Dynamics Simulations and Quantum Mechanical Calculations: The Effect of Cation’s Shape and Size

Influence of Ionic Liquids on the Aggregation and Preaggregation Phenomena of Asphaltenes in Model Solvent Mixtures by Molecular Dynamics Simulations and Quantum Mechanical Calculations: The Effect of Cation’s Shape and Size

QM/MM study of the catalytic reaction of aphid myrosinase

Brevicoryne brassicae, an aphid species, exclusively consumes plants from the Brassicaceae family and employs a sophisticated defense mechanism involving a myrosinase enzyme that breaks down glucosinolates obtained from its host plants. In this work, we employed combined quantum mechanical and molecular mechanical (QM/MM) calculations and molecular dynamics (MD) simulations to study the catalytic reaction of aphid myrosinase. A proper QM region to study the myrosinase reaction should contain the whole substrate, models of Gln-19, His-122, Asp-124, Asn-166, Glu-167, Lys-173, Tyr-180, Val-228, Tyr-309, Tyr-346, Ile-347, Glu-374, Glu-423, Trp-424, and a water molecule. The calculations show that Asp-124 and Glu-423 must be charged, His-122 must be protonated on NE2, and Glu-167 must be protonated on OE2. Our model reproduces the anomeric retaining characteristic of myrosinase and indicates that the deglycosylation reaction is the rate-determining step of the reaction. Based on the calculations, we propose a reaction mechanism for aphid myrosinase-mediated hydrolysis of glucosinolates with an overall barrier of 15.2 kcal/mol. According to the results, removing a proton from Arg-312 or altering it to valine or methionine increases glycosylation barriers but decreases the deglycosylation barrier.

Design of human ACE2 mimic miniprotein binders that interact with RBD of SARS-CoV-2 variants of concerns

The world of medicine demands from the research community solutions to the emerging problem of SARS-CoV-2 variants and other such potential global pandemics. With advantages of specificity over small molecule drugs and designability over antibodies, miniprotein therapeutics offers a unique solution to the threats of rapidly emerging SARS-CoV-2 variants. Unfortunately, most of the promising miniprotein binders are de novo designed and it is not viable to generate molecules for each new variant. Therefore in this study, we demonstrate a method for design of miniprotein mimics from the interaction interphase of human angiotensin converting enzyme 2 (ACE2). ACE2 is the natural interacting partner for the SARS-CoV-2 spike receptor binding domain (RBD) and acts as a recognition molecule for viral entry into the host cells. Starting with ACE2 N-terminal triple helix interaction interphase, we generated more than 70 miniprotein sequences. Employing Rosetta folding and docking scores we selected 10 promising miniprotein candidates amongst which 3 were found to be soluble in lab studies. Further, using molecular mechanics (MM) calculations on molecular dynamics (MD) trajectories we test interaction of miniproteins with RBD from various variants of concern (VOC). Presently, we report two key findings; miniproteins in this study are generated using less than 10 lab testing experiments, yet when tested through in-vitro experiments, they show submicro to nanomolar affinities towards SARS-CoV-2 RBD. Also in simulation studies, when compared with previously developed therapeutics, our miniproteins display remarkable ability to mimic ACE2 interphase; making them an ideal solution to the ever evolving problem of VOCs. Communicated by Ramaswamy H. Sarma

Enzyme Engineering Renders Chlorinase the Activity of Fluorinase.

Organofluorine compounds have attracted substantial attention owing to their wide application in agrochemistry. Fluorinase (FlA) is a unique enzyme in nature that can incorporate fluorine into an organic molecule. Chlorinase (SalL) has a similar mechanism as fluorinase and can use chloride but not fluoride as a substrate to generate 5'-chloro-deoxyadenosine (5'-ClDA) from S-adenosyl-l-methionine (SAM). Therefore, identifying the features that lead to this selectivity for halide ions is highly important. Here, we engineered SalL to gain the function of FlA. We found that residue Tyr70 plays a key role in this conversion through alanine scanning. Site-saturation mutagenesis experiments demonstrated that Y70A/C/S/T/G all exhibited obvious fluorinase activity. The G131S mutant of SalL, in which the previously thought crucial residue Ser158 for fluoride binding in FlA was introduced, did not exhibit fluorination activity. Compared with the Y70T single mutant, the double mutant Y70T/W129F increased 5'-fluoro-5-deoxyadenosine (5'-FDA) production by 76%. The quantum mechanics (QM)/molecular mechanics (MM) calculations suggested that the lower energy barriers and shorter nucleophilic distance from F- to SAM in the mutants than in the SalL wild-type may contribute to the activity. Therefore, our study not only renders SalL the activity of FlA but also sheds light on the enzyme selectivity between fluoride versus chloride.

Investigation of the effects of solvent on oxygen evolution reactions on the surface of magnesium oxide

In this research, due to the importance of oxygen evolution reactions (OER) in the production of hydrogen gas, the effects of the solvent on the OER steps on the magnesium oxide surface have been studied. For this purpose, the difference in free energy value in OER steps on the Magnesium oxide surface for two systems (in the presence and the absence of solvent) have been investigated using molecular dynamics (MD) simulation and thermodynamic integration (TI). These results are in perfect agreement with the results obtained from ab initio molecular dynamics simulations and quantum mechanics calculations. Our findings show that the presence of water solvent around the surface of magnesium oxide has a crucial role on OER and leads to an increase more than twofold in the free energy of all steps. Also, the presence of the solvent has the most effect on the third step of OER, and its ΔG increases by about 1.9 eV. This fact can be attributed to the approach of the water molecules to the substrate spontaneously, which increases the probability of forming hydrogen bonds and the number of contacts, leading to more favorable thermodynamic reactions. Close inspection of the calculated binding energies between the substrate and the intermediates confirms that the binding energy of OER's second step is significantly higher than the other steps and is the velocity determining step.