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Nucleophilic fluorination of aromatic rings can be done via a cross-coupling reaction catalyzed by palladium and biaryl monophosphine ligands such as AlPhos. Nevertheless, aromatic fluorination via palladium catalysis can lead to regioisomers, a serious problem for this kind of reaction. An ortho-deprotonation mechanism was proposed for this reaction in previous studies. However, this mechanism does not explain why the ortho product is not formed from para and meta substrates, and the details of the mechanism are not fully understood yet. This theoretical work discloses the mechanism behind regioisomers formation, which takes place via unimolecular ortho-elimination of HF. The computed free energy profile of the reaction was followed by a detailed microkinetic analysis, which explain the experiments quantitatively. The present study shows that the rotation of the aryne coordinated to the palladium to form a complex leading to the ortho product is critical for regioselectivity. This rotation has a high free energy barrier due to steric repulsion with the adamantane group of the ligand. Such a feature impedes the formation of ortho product from para and meta substrates and allows the formation of the ortho product selectively from the ortho substrate. [ABSTRACT FROM AUTHOR]

Cholinesterases are well‐known and widely studied enzymes crucial to human health and involved in neurology, Alzheimer's, and lipid metabolism. The protonation pattern of active sites of cholinesterases influences all the chemical processes within, including reaction, covalent inhibition by nerve agents, and reactivation. Despite its significance, our comprehension of the fine structure of cholinesterases remains limited. In this study, we employed enhanced‐sampling quantum‐mechanical/molecular‐mechanical calculations to show that cholinesterases predominantly operate as dynamic mixtures of two protonation states. The proton transfer between two non‐catalytic glutamate residues follows the Grotthuss mechanism facilitated by a mediator water molecule. We show that this uncovered complexity of active sites presents a challenge for classical molecular dynamics simulations and calls for special treatment. The calculated proton transfer barrier of 1.65 kcal/mol initiates a discussion on the potential existence of two coupled low‐barrier hydrogen bonds in the inhibited form of butyrylcholinesterase. These findings expand our understanding of structural features expressed by highly evolved enzymes and guide future advances in cholinesterase‐related protein and drug design studies. [ABSTRACT FROM AUTHOR]

Context: Nucleophilic substitution reactions of aliphatic amines with alkyl halides represent a simple and direct mechanism for obtaining higher-order aliphatic amines. However, it is well known that these reactions suffer from low selectivity due to multiple alkylations, which is attributed to the higher reactivity of the newly formed amine. In order to provide a detailed explanation for this kind of system, we have investigated the reactivity of primary and secondary amines with 1-bromopropane and 2-bromopropane. The free energy profile in acetonitrile solution was obtained and a detailed microkinetic analysis was needed to analyze this complex reaction system. We have found that the product of the first alkylation is an ion pair corresponding to the protonated secondary amine and the bromide ion, which can transfer the proton to the reactant primary amine. Then, the newly formed secondary amine can also react, leading to a second alkylation to produce a tertiary protonated amine. Our modeling points out that both the proton transfer equilibria and the similar reactivity of the primary and secondary amines produce reduced selectivity. The proton transfer equilibria also contribute to slowing down the kinetics of the first alkylation. Methods: The exploration of the mechanism was done by geometry optimization using the CPCM/X3LYP/ma-def2-SVP method, followed by harmonic frequency calculation at this same level of theory. A composite approach was used to obtain the free energy profile, using the more accurate ωB97X-D3/ma-def2-TZVPP level of theory for electronic energy and the SMD model for the solvation free energy. These calculations were performed with the ORCA 4 program. The detailed microkinetic analysis was done using the Kintecus program. [ABSTRACT FROM AUTHOR]

The emergence of multi-drug-resistant tuberculosis strains poses a significant challenge to modern medicine. The development of new antituberculosis drugs is hindered by the low permeability of many active compounds through the extremely strong bacterial cell wall of mycobacteria. In order to estimate the ability of potential antimycobacterial agents to diffuse through the outer mycolate membrane, the free energy profiles, the corresponding activation barriers, and possible permeability modes of passive transport for a series of known antibiotics, modern antituberculosis drugs, and prospective active drug-like molecules were determined using molecular dynamics simulations with the all-atom force field and potential of mean-force calculations. The membranes of different chemical and conformational compositions, density, thickness, and ionization states were examined. The typical activation barriers for the low-mass molecules penetrating through the most realistic membrane model were 6–13 kcal/mol for isoniazid, pyrazinamide, and etambutol, and 19 and 25 kcal/mol for bedaquilin and rifampicin. The barriers for the ionized molecules are usually in the range of 37–63 kcal/mol. The linear regression models were derived from the obtained data, allowing one to estimate the permeability barriers from simple physicochemical parameters of the diffusing molecules, notably lipophilicity and molecular polarizability. [ABSTRACT FROM AUTHOR]

The bacterial adhesin FimH is a model for the study of protein allostery because its structure has been resolved in multiple configurations, including the active and the inactive state. FimH consists of a pilin domain (PD) that anchors it to the rest of the fimbria and an allosterically regulated lectin domain (LD) that binds mannose on the surface of infected cells. Under normal conditions, the two domains are docked to each other and LD binds mannose weakly. However, in the presence of tensile force generated by shear the domains separate and conformational changes propagate across LD resulting in a stronger bond to mannose. Recently, the crystallographic structure of a variant of FimH has been resolved, called FimHFocH, where PD contains 10 mutations near the inter‐domain interface. Although the X‐ray structures of FimH and FimHFocH are almost identical, experimental evidence shows that FimHFocH is activated even in the absence of shear. Here, molecular dynamics simulations combined with the Jarzynski equality were used to investigate the discrepancy between the crystallographic structures and the functional assays. The results indicate that the free energy barrier of the unbinding process between LD and PD is drastically reduced in FimHFocH. Rupture of inter‐domain hydrogen bonds involving R166 constitutes a rate limiting step of the domain separation process and occurs more readily in FimHFocH than FimH. In conclusion, the mutations in FimHFocH shift the equilibrium toward an equal occupancy of bound and unbound states for LD and PD by reducing a rate limiting step. [ABSTRACT FROM AUTHOR]

Partially reduced silver clusters growing in a polycytosine matrix could simultaneously possess stabilizing ability and remarkable optical features. The mechanisms of this phenomenon are not fully understood so far. We examined the thermodynamic stability of a cytosine–silver associate comprising four cytosines and three silver atoms that can be considered the smallest known luminescent silver marker stabilized on DNA. Quantum and molecular mechanical representations thermodynamic integration toward the dissociation pathway of the cytosine tetramer, time‐dependent density functional theory calculations of the lowest energy excited states and quantum theory of atoms in molecules analysis of bonding showed that the reduction of two ions within the silver trimer mediating cytosine tetramer leads to the appearance of the green‐emitting silver cluster with low stabilization ability of cytosines relative to a tetramer stabilized by two silver ions. [ABSTRACT FROM AUTHOR]

The potential of cold atmospheric plasma (CAP) in biomedical applications has received significant interest, due to its ability to generate reactive oxygen and nitrogen species (RONS). Upon exposure to living cells, CAP triggers alterations in various cellular components, such as the cell membrane. However, the permeation of RONS across nitrated and oxidized membranes remains understudied. To address this gap, we conducted molecular dynamics simulations, to investigate the permeation capabilities of RONS across modified cell membranes. This computational study investigated the translocation processes of less hydrophilic and hydrophilic RONS across the phospholipid bilayer (PLB), with various degrees of oxidation and nitration, and elucidated the impact of RONS on PLB permeability. The simulation results showed that less hydrophilic species, i.e., NO, NO2, N2O4, and O3, have a higher penetration ability through nitro-oxidized PLB compared to hydrophilic RONS, i.e., HNO3, s-cis-HONO, s-trans-HONO, H2O2, HO2, and OH. In particular, nitro-oxidation of PLB, induced by, e.g., cold atmospheric plasma, has minimal impact on the penetration of free energy barriers of less hydrophilic species, while it lowers these barriers for hydrophilic RONS, thereby enhancing their translocation across nitro-oxidized PLB. This research contributes to a better understanding of the translocation abilities of RONS in the field of plasma biomedical applications and highlights the need for further analysis of their role in intracellular signaling pathways. [ABSTRACT FROM AUTHOR]

The early characterization of drug membrane permeability is an important step in pharmaceutical developments to limit possible late failures in preclinical studies. This is particularly crucial for therapeutic peptides whose size generally prevents them from passively entering cells. However, a sequence-structure-dynamics-permeability relationship for peptides still needs further insight to help efficient therapeutic peptide design. In this perspective, we conducted here a computational study for estimating the permeability coefficient of a benchmark peptide by considering and comparing two different physical models: on the one hand, the inhomogeneous solubility–diffusion model, which requires umbrella–sampling simulations, and on the other hand, a chemical kinetics model which necessitates multiple unconstrained simulations. Notably, we assessed the accuracy of the two approaches in relation to their computational cost. [ABSTRACT FROM AUTHOR]

NHC‐catalyzed Stetter‐aldol reaction for the synthesis of hydroxyindanone takes place via umpolung reactions of phthalaldehyde followed by intramolecular aldol reaction when N‐tert‐butoxycarbonyl (Boc) imine is used and this leads to the formation of [4+1] annulation product. However, this mechanism doesn't follow similar sequence in case of N‐tosyl‐α,β‐unsaturated ketimine and [4+2]‐annulation product is found as the sole product for the latter case through formation of aza‐"Berslow intermediate". In this study we have used state of the art computational techniques to find out the possible reason for the difference in product and the detailed mechanistic pathway for the above two reactions. Thus, we explain the mechanism for obtaining the selective annulation product ([4+1] vs [4+2]) that can help chemists to design and synthesize a new series of compounds. [ABSTRACT FROM AUTHOR]

The potential of cold atmospheric plasma (CAP) in biomedical applications has received significant interest, due to its ability to generate reactive oxygen and nitrogen species (RONS). Upon exposure to living cells, CAP triggers alterations in various cellular components, such as the cell membrane. However, the permeation of RONS across nitrated and oxidized membranes remains understudied. To address this gap, we conducted molecular dynamics simulations, to investigate the permeation capabilities of RONS across modified cell membranes. This computational study investigated the translocation processes of less hydrophilic and hydrophilic RONS across the phospholipid bilayer (PLB), with various degrees of oxidation and nitration, and elucidated the impact of RONS on PLB permeability. The simulation results showed that less hydrophilic species, i.e., NO, NO2, N2O4, and O3, have a higher penetration ability through nitro-oxidized PLB compared to hydrophilic RONS, i.e., HNO3, s-cis-HONO, s-trans-HONO, H2O2, HO2, and OH. In particular, nitro-oxidation of PLB, induced by, e.g., cold atmospheric plasma, has minimal impact on the penetration of free energy barriers of less hydrophilic species, while it lowers these barriers for hydrophilic RONS, thereby enhancing their translocation across nitro-oxidized PLB. This research contributes to a better understanding of the translocation abilities of RONS in the field of plasma biomedical applications and highlights the need for further analysis of their role in intracellular signaling pathways.

Due to their potential benefits, cold atmospheric plasmas (CAPs), as biotechnological tools, have been used for various purposes, especially in medical and agricultural applications. The main effect of CAP is associated with reactive oxygen and nitrogen species (RONS). In order to deliver these RONS to the target, direct or indirect treatment approaches have been employed. The indirect method is put into practice via plasma-activated water (PAW). Despite many studies being available in the field, the permeation mechanisms of RONS into water at the molecular level still remain elusive. Here, we performed molecular dynamics simulations to study the permeation of RONS from vacuum into the water interface and bulk. The calculated free energy profiles unravel the most favourable accumulation positions of RONS. Our results, therefore, provide fundamental insights into PAW and RONS chemistry to increase the efficiency of PAW in biological applications. [ABSTRACT FROM AUTHOR]

The reactivity of the fluoride ion towards alkyl halides is highly dependent on the solvating environment. In polar aprotic solvents with large counter-ions is highly reactive and produces substantial E2 product, whereas in polar protic solvents leads to slow kinetics and high selectivity for SN2 reactions. The use of a more complex environment with stoichiometric addition of tert-butanol to acetonitrile solvent is able to module the reactivity and selectivity of tetrabutylammonium fluoride (TBAF). In the present work, we have performed a detailed theoretical analysis of this complex reaction system by density functional theory, continuum solvation model, and including explicit tert-butanol molecules. A kinetic model based on the free energy profile was also used to predict the reactivity and selectivity. The results indicated that the TBAF(tert-butanol) complex plays the key role to increase the SN2 selectivity, whereas higher aggregates are not relevant. The E2 product is formed exclusively via free TBAF, because the solvating tert-butanol in the TBAF(tert-butanol) complex inhibits the E2 pathway. Our analysis suggests that diols or tetraols could produce an improved selectivity. [ABSTRACT FROM AUTHOR]

This study investigates the absorption mechanisms of carbon dioxide (CO 2), hydrogen sulfide (H 2 S), and methane (CH 4) molecules in two imidazolium-based ionic liquids, namely 1-ethyl-3-methylimidazolium thiocyanate ([EMIM][SCN]) and 1-ethyl-3-methylimidazolium dicyanamide ([EMIM][DCA]). We employed molecular dynamics (MD) simulations applying umbrella sampling technique to calculate free energy profiles (FEPs) for gas molecules in the ILs. The results reveal CO 2 's pronounced affinity for the interface over the bulk in both ionic liquids (IL), whereas H 2 S exhibits facile penetration into both regions. CH 4 shows limited penetration into the IL bulk, remaining predominantly near the interface. We further explore the influence of ILs' anionic structures on gas accumulation sites by performing normal MD simulations. For instance, density profiles also confirm CO 2 's higher density in [EMIM][DCA] compared to [EMIM][SCN], reflecting the influence of anionic composition on CO 2 solubility. These insights offer valuable knowledge for designing efficient ILs for gas capture and separation applications. [ABSTRACT FROM AUTHOR]

The early characterization of drug membrane permeability is an important step in pharmaceutical developments to limit possible late failures in preclinical studies. This is particularly crucial for therapeutic peptides whose size generally prevents them from passively entering cells. However, a sequence-structure-dynamics-permeability relationship for peptides still needs further insight to help efficient therapeutic peptide design. In this perspective, we conducted here a computational study for estimating the permeability coefficient of a benchmark peptide by considering and comparing two different physical models: on the one hand, the inhomogeneous solubility–diffusion model, which requires umbrella–sampling simulations, and on the other hand, a chemical kinetics model which necessitates multiple unconstrained simulations. Notably, we assessed the accuracy of the two approaches in relation to their computational cost.

Calcium-release-activated calcium (CARC) channels are one of the major pathways of calcium entry in non-excitable cells. Despite a decade or two of research, its regulatory mechanism is not yet thoroughly understood. The slow progress is due to the complexity of its pores (i.e., Orai) on one hand and the difficulty in capturing its regulatory complex on the other hand. As a result, possible gating mechanisms have often been speculated by exploring the structure and properties of constitutive open mutants. However, there is much debate about how they can truly reflect the gating of CRAC channels under physiological conditions. In the present study, we combined molecular dynamics simulations with free energy calculations to study three dOrai mutants (G170P, H206A, and P288A), and further calculated their current-voltage curves. Results show that these constructs adopt different approaches to maintain their conductive state. Meanwhile they have unique pore structures and distinctive rectification properties and ion selectivity for cations compared to wild-type pores. We conclude that although the mutants may partially capture the gating motion characteristics of wild-type pores, the information obtained from these mutants is likely not a true reflection of CRAC channel gating under physiological conditions. [ABSTRACT FROM AUTHOR]

Cholinesterases are well-known and widely studied enzymes crucial to human health and involved in neurology, Alzheimer's, and lipid metabolism. The protonation pattern of active sites of cholinesterases influences all the chemical processes within, including reaction, covalent inhibition by nerve agents, and reactivation. Despite its significance, our comprehension of the fine structure of cholinesterases remains limited. In this study, we employed enhanced-sampling quantum-mechanical/molecular-mechanical calculations to show that cholinesterases predominantly operate as dynamic mixtures of two protonation states. The proton transfer between two non-catalytic glutamate residues follows the Grotthuss mechanism facilitated by a mediator water molecule. We show that this uncovered complexity of active sites presents a challenge for classical molecular dynamics simulations and calls for special treatment. The calculated proton transfer barrier of 1.65 kcal/mol initiates a discussion on the potential existence of two coupled low-barrier hydrogen bonds in the inhibited form of butyrylcholinesterase. These findings expand our understanding of structural features expressed by highly evolved enzymes and guide future advances in cholinesterase-related protein and drug design studies., (© 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Oleanolic acid is a widely distributed natural product, which possesses promising antitumor, antiviral, antihyperlipidemic, and anti-inflammatory activities. A heterodimeric complex formed by integrin αM (CD11b) and integrin β2 (CD18) is highly expressed on monocytes and macrophages. In the current study, we demonstrate that the I domain of αM (αM-I domain) might present a potential cellular target for oleanolic acid. In vitro data show that oleanolic acid induces clustering of αM on macrophages and reduces their non-directional migration. In accordance with experimental data, molecular docking revealed that oleanolic acid binds to the αM-I domain in its extended-open form, the dominant conformation found in αM clusters. Molecular dynamics simulation revealed that oleanolic acid can increase the flexibility of the α7 helix and promote its movement away from the N-terminus, indicating that oleanolic acid may facilitate the conversion of the αM-I domain from the extended-closed to the extended-open conformation. As demonstrated by metadynamics simulation, oleanolic acid can destabilize the local minimum of the αM-I domain in the open conformation partially through disturbance of the interactions between α1 and α7 helices. In summary, we demonstrate that oleanolic acid might function as an allosteric agonist inducing clustering of αM on macrophages by shifting the balance from the closed to the extended-open conformation. The molecular target identified in this study might hold potential for a purposeful use of oleanolic acid to modulate chronic inflammatory responses. [ABSTRACT FROM AUTHOR]

Oleanolic acid is a widely distributed natural product, which possesses promising antitumor, antiviral, antihyperlipidemic, and anti-inflammatory activities. A heterodimeric complex formed by integrin αM (CD11b) and integrin β2 (CD18) is highly expressed on monocytes and macrophages. In the current study, we demonstrate that the I domain of αM (αM-I domain) might present a potential cellular target for oleanolic acid. In vitro data show that oleanolic acid induces clustering of αM on macrophages and reduces their non-directional migration. In accordance with experimental data, molecular docking revealed that oleanolic acid binds to the αM-I domain in its extended-open form, the dominant conformation found in αM clusters. Molecular dynamics simulation revealed that oleanolic acid can increase the flexibility of the α7 helix and promote its movement away from the N-terminus, indicating that oleanolic acid may facilitate the conversion of the αM-I domain from the extended-closed to the extended-open conformation. As demonstrated by metadynamics simulation, oleanolic acid can destabilize the local minimum of the αM-I domain in the open conformation partially through disturbance of the interactions between α1 and α7 helices. In summary, we demonstrate that oleanolic acid might function as an allosteric agonist inducing clustering of αM on macrophages by shifting the balance from the closed to the extended-open conformation. The molecular target identified in this study might hold potential for a purposeful use of oleanolic acid to modulate chronic inflammatory responses.

The development of structured molecular systems based on a nucleic acid framework takes into account the ability of single-stranded DNA to form a stable double-stranded structure due to stacking interactions and hydrogen bonds of complementary pairs of nucleotides. To increase the stability of the DNA double helix and to expand the temperature range in the hybridization protocols, it was proposed to use more stable metal-mediated complexes of nucleotide pairs as an alternative to Watson-Crick hydrogen bonds. One of the most frequently considered options is the use of silver ions to stabilize a pair of cytosines from opposite DNA strands. Silver ions specifically bind to N3 cytosines along the helix axis to form, as is believed, a strong N3-Ag+-N3 bond, relative to which, two rotational isomers, the cis- and trans-configurations of C-Ag+-C can be formed. In present work, a theoretical study and a comparative analysis of the free energy profile of the dissociation of two С-Ag+-C isomers were carried out using the combined method of molecular mechanics and quantum chemistry (QM/MM). As a result, it was shown that the cis-configuration is more favorable in energy than the trans- for a single pair of cytosines, and the geometry of the global minimum at free energy profile for both isomers differs from the equilibrium geometries obtained previously by quantum chemistry methods. Apparently, the silver ion stabilization model of the DNA duplex should take into account not only the direct binding of silver ions to cytosines, but also the presence of related factors, such as stacking interaction in extended DNA, interplanar hydrogen bonds, and metallophilic interaction of neighboring silver ions.

Due to their potential benefits, cold atmospheric plasmas (CAPs), as biotechnological tools, have been used for various purposes, especially in medical and agricultural applications. The main effect of CAP is associated with reactive oxygen and nitrogen species (RONS). In order to deliver these RONS to the target, direct or indirect treatment approaches have been employed. The indirect method is put into practice via plasma-activated water (PAW). Despite many studies being available in the field, the permeation mechanisms of RONS into water at the molecular level still remain elusive. Here, we performed molecular dynamics simulations to study the permeation of RONS from vacuum into the water interface and bulk. The calculated free energy profiles unravel the most favourable accumulation positions of RONS. Our results, therefore, provide fundamental insights into PAW and RONS chemistry to increase the efficiency of PAW in biological applications.

Ba(Zr0.2Ti0.8)O3-x(Ba0.7Ca0.3)TiO3 (BZT-xBCT) is a promising lead-free ferroelectric system with high piezoelectricity. Here we carry out phenomenological calculations to explore phase stability and electric field induced phase transition. Study of free energy variation near phase boundaries revealed ultralow energy barrier in single orthorhombic phase region and phase coexistence around inter-ferroelectric transitions. The calculated critical electric field for tetragonal-orthorhombic transition is in reasonable agreement with experimental data. Temperature–composition phase diagram under [001], [011] and [111] oriented electric field are computed, and polarization rotation associated monoclinic structures are studied. [ABSTRACT FROM AUTHOR]

Ba(Zr0.2Ti0.8)O3-x(Ba0.7Ca0.3)TiO3 (BZT-xBCT) is a promising lead-free ferroelectric system with high piezoelectricity. Here we carry out phenomenological calculations to explore phase stability and electric field induced phase transition. Study of free energy variation near phase boundaries revealed ultralow energy barrier in single orthorhombic phase region and phase coexistence around inter-ferroelectric transitions. The calculated critical electric field for tetragonal-orthorhombic transition is in reasonable agreement with experimental data. Temperature–composition phase diagram under [001], [011] and [111] oriented electric field are computed, and polarization rotation associated monoclinic structures are studied. [ABSTRACT FROM AUTHOR]

Understanding the mechanisms of petroleum thermal cracking is critical to develop more efficient and eco-friendly petroleum cracking processes. Asphaltenes are the main component of petroleum subjected to cracking processes. Thermal cracking mechanisms of petroleum were explored by computational methods using 1,2-diphenylethane (DPE) as a model molecule in this study. The overall mechanisms were divided into four steps including initiation, H-transfer reaction, H-ipso reaction, and termination represented by seven reactions. We carried out extensive quantum chemistry calculations at high levels of theory to accurately explore the minimum energy pathways as the mechanisms of the proposed reactions. The reaction energy and barriers in terms of enthalpy and free energy and their temperature dependence were calculated in the vacuum and in both polar and nonpolar solvents using the polarizable continuum model (PCM) method. The temperature dependence of the target reaction barriers are characterized in different environments and provides computational guidance for future development for petroleum thermal cracking. As the first reported systematic investigation of petroleum cracking mechanisms, this study provided a comprehensive theoretical description of petroleum cracking processes with valuable information about temperature and solvent dependence. [ABSTRACT FROM AUTHOR]

(1) Background: Currently, nanomaterials have been broadly used in various applications including engineering, medicine and biology. One of the carbon allotropes such as carbon nanotubes (CNTs) implemented for fabrication of nanocomposite materials due to the hypersensitivity. The combined design of nanomaterial with chitosan (CS) and CNT expands the field of exploitation from biosensing and tissue engineering to water desalination. Therefore, the penetration of CS into CNT provides a valuable insight into the interactions between CS and CNT. (2) Methods: We performed molecular dynamics simulations, applying the umbrella sampling method, in order to calculate the potential mean force between CS and CNT. (3) Results: The estimated penetration free energies showed that CS is favorable to the penetration into CNT cavities. However, the penetration nature differs depending on the CNT’s architecture. (4) Conclusions: Our finding revealed the CS penetration process into CNT with nanoscale precision. The investigation results assist in a better understanding of the nanocomposite materials based on CS-CNT.

Background: Arsenic has a broad anti-cancer ability against hematologic malignancies and solid tumors. To systematically understand the biological functions of arsenic, we need to identify arsenic-binding proteins in human cells. However, due to lack of effective theoretical tools and experimental methods, only a few arsenic-binding proteins have been identified. Methods: Based on the crystal structure of ArsM, we generated a single mutation free energy profile for arsenic binding using free energy perturbation methods. Multiple validations provide an indication that our computational model has the ability to predict arsenic-binding proteins with desirable accuracy. We subsequently apply this computational model to scan the entire human genome to identify all the potential arsenic-binding proteins. Results: The computationally predicted arsenic-binding proteins show a wide range of biological functions, especially in the signaling transduction pathways. In the signaling transduction pathways, arsenic directly binds to the key factors (e.g., Notch receptors, Notch ligands, Wnt family proteins, TGF-beta, and their interacting proteins) and results in significant inhibitions on their enzymatic activities, further having a crucial impact on the related signaling pathways. Conclusions: Arsenic has a significant impact on signaling transduction in cells. Arsenic binding to proteins can lead to dysfunctions of the target proteins, having crucial impacts on both signaling pathway and gene transcription. We hope that the computationally predicted arsenic-binding proteins and the functional analysis can provide a novel insight into the biological functions of arsenic, revealing a mechanism for the broad anti-cancer of arsenic. [ABSTRACT FROM AUTHOR]

Molecular recognition of the amphiphilic electron carrier ubiquinone (Q) by respiratory complexes is a fundamental part of electron transfer chains in mitochondria and bacteria. The primary respiratory complex I binds Q in a long and narrow protein chamber to catalyse its reduction. But, the binding mechanism and the role of chamber hydration in substrate selectivity and stability are unclear. Here, large-scale atomistic molecular dynamics simulations and estimated free energy profiles are used to characterize in detail the binding mechanism to complex I of Q with short and with long isoprenoid tails. A highly stable binding site with two different poses near the chamber exit and a secondary reactive site near the N2 iron-sulfur cluster are found which may lead to an alternative Q redox chemistry and help to explain complex I reactivity. The binding energetics depends mainly on polar interactions of the Q-head and on the counterbalanced hydration of Q-tail isoprenoid units and hydrophobic residues inside the protein chamber. Selectivity upon variation of tail length arises by shifting the hydration balance. This internal hydration mechanism may have implications for binding of amphiphilic molecules to cavities in other membrane proteins. Unlabelled Image • Ubiquinone binding to complex I studied with molecular dynamics and free energy simulations • A highly stable binding site found with two different poses near the complex I chamber exit • Binding energetics depends on polar contacts and a counterbalanced hydration of hydrophobic regions. • Quinones with short isoprenoid tail shift this hydration balance. [ABSTRACT FROM AUTHOR]

The equilibrium and nonequilibrium adaptive alchemical free energy simulation methods optimum Bennett's acceptance ratio and optimum crooks' equation (OCE), based on the statistically optimal bidirectional reweighting estimator named Bennett's Acceptance Ratio or Crooks' equation, perform initial sampling in the staging alchemical transformation and then determine the importance rank of different states via the time‐derivative of the variance. The method is proven to give speedups compared with the equal time rule. In the current work, we extend the time derivative of variance guided adaptive sampling method to the configurational space, falling in the term of steered MD (SMD). The SMD approach biasing physically meaningful collective variable (CV) such as one dihedral or one distance to pulling the system from one conformational state to another. By minimizing the variance of the free energy differences along the pathway in an optimized way, a new type of adaptive SMD (ASMD) is introduced. As exhibits in the alchemical case, this adaptive sampling method outperforms the traditional equal‐time SMD in nonequilibrium stratification. Also, the method gives much more efficient calculation of potential of mean force than the selection criterion‐based ASMD scheme, which is proven to be more efficient than traditional SMD. The OCE workflow is periodicity‐of‐CV dependent while ASMD is not. The performance is demonstrated in a dihedral flipping case and two distance pulling cases, accounting for periodic and nonperiodic CVs, respectively. © 2019 Wiley Periodicals, Inc. The adaptive nonequilibrium pulling scheme introduced in this work, the global optimum Crooks' equation (GOCE) method, is based on the statistically optimal and asymptotically unbiased estimator of Crooks' equation. GOCE achieves about an order of magnitude speedup in the construction of the free energy landscapes, compared with the previously proposed adaptive steered molecular dynamics method. The nonequal time rule used in GOCE leads to onefold speedup in minimizing the statistical uncertainty along the free energy profiles. As a result, the GOCE scheme is one of the fastest nonequilibrium pulling method for the construction of free energy landscapes. The approach is tested in three biologically relevant cases. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • DFT employed gas phase detoxication of Tabun (nerve agent) has been explored. • Energetics of assisted detoxication pathways are compared with unimolecular processes. • RDS of each assisted pathway is ∼20.0 kcal/mol lower than the respective unimolecular process. • γ-H assisted decomposition process is the most favored detoxication pathway. • ZrO 2 acts as better assisting reagent than TiO 2. Abstract In this study, the gas phase MO 2 (M = Ti, Zr) assisted detoxication of tabun (nerve agent) is explored by employing DFT, where the energetics of assisted pathways are compared with the respective unimolecular pathways. A total of six detoxication pathways are explored among which γ-H assisted decomposition pathway is the most favored one. The activation barrier of the rate determining step (RDS) of each assisted detoxication pathways is significantly lower than that of the respective unimolecular pathway. Among two assisting reagents, the assisting capability of ZrO 2 is found to be better than that of TiO 2. [ABSTRACT FROM AUTHOR]

Graphical abstract Legend: Ascorbic acid (white) has steric clashed with NADH (orange) and leads to gulonate-3-dehydrogenase inhibition. Highlights • Molecular dockings of ascorbate to gulonate-3-dehydrogenase indicated its binding near the co-factor binding site. • Docking revealed that ascorbate binding could lead to steric clashes between ascorbate and the co-factor (NADH). • Molecular dynamics simulations confirm interaction of ascorbic acid at the co-factor binding site. • Ascorbate's binding negatively affects further binding of NADH to and enzymatic functions of gulonate-3-dehydrogenase. • These observations depict a possible mechanism of gulonate-3-dehydrogenase inhibition by ascorbic acid. Abstract l -Gulonate dehydrogenase (GuDH) is a crucial enzyme in the non-phosphorylated sugar metabolism or glucuronate-xylulose (GX) pathway. Some naturally occurring compounds inhibit GuDH. Ascorbic acid is one of such inhibitors for GuDH. However, the exact mechanism by which ascorbic acid inhibits GuDH is still unknown. In this study, we try to investigate GuDH inhibition using computational approaches by generating a model for buffalo GuDH. We used this model to perform blind dockings of ascorbic acid to GuDH. Some docked conformations of ascorbic acid bind near Asp39 and have steric clashes with crystal structure conformation of NADH. To assess the dynamic stability of the GuDH-ascorbic acid complex, we performed six molecular dynamics simulations for GuDH, three each in its free form and in complex with ascorbic acid for 50 ns, to obtain 300 ns of trajectories in total. During the simulations, ascorbic acid interacted with several residues nearby Asp39. As Asp39 is an important residue for NADH binding and specificity, the interaction of ascorbic acid near Asp39 hinders further NADH binding and ultimately affects the enzymatic functioning of GuDH. In this study, we analyze these interactions between ascorbic acid and GuDH. Our analysis reveals novel details on the mechanism of GuDH inhibition by ascorbic acid. [ABSTRACT FROM AUTHOR]

We present a computational study on the enantioselectivity of organocatalytic proline-catalyzed aldol reactions between aldehydes in dimethylformamide (DMF). To explore the free energy surface of the reaction, we apply two-dimensional metadynamics on top of ab initio molecular dynamics (AIMD) simulations with explicit solvent description on the DFT level of theory. We avoid unwanted side reactions by utilizing our newly developed hybrid AIMD (HyAIMD) simulation scheme, which adds a simple force field to the AIMD simulation to prevent unwanted bond breaking and formation. Our condensed phase simulation results are able to nicely reproduce the experimental findings, including the main stereoisomer that is formed, and give a correct qualitative prediction of the change in syn:anti product ratio with different substituents. Furthermore, we give a microscopic explanation for the selectivity. We show that both the explicit description of the solvent and the inclusion of entropic effects are vital to a good outcome—metadynamics simulations in vacuum and static nudged elastic band (NEB) calculations yield significantly worse predictions when compared to the experiment. The approach described here can be applied to a plethora of other enantioselective or organocatalytic reactions, enabling us to tune the catalyst or determine the solvent with the highest stereoselectivity.

[Display omitted] • Detailed microkinetic analysis explain the product ratio. • Electrophilic mechanism does not explain aromatic bromination in apolar solvent. • Electron-withdrawing groups in the aromatic ring decrease the reaction rate. • Oxygen and nitrogen atoms bonded to the benzylic carbon accelerate the reaction. Halogenation of organic compounds is an important functionalization process for further chemical transformation and the benzylic hydrogen is reactive towards the photochemically generated Br atom. This work reports the free energy profile of the several steps of the reaction of the Br atom with toluene leading to benzyl bromide, (dibromomethyl)benzene, and (tribromomethyl)benzene using reliable theoretical B2GP-PLYP method. A detailed microkinetic analysis of the reaction rate and product distribution was also performed. Our analysis points out that polar solvent increases the reaction rate in relation to apolar one. Substitution on the aromatic ring cannot be explained by the electrophilic mechanism in an apolar medium. The reactivity of different benzylic substrates was evaluated, and we have found that the cyano electron-withdrawing group in the aromatic ring retards the reaction, while the ortho -methoxy group, and oxygen and nitrogen atoms bonded to the benzylic carbon, enhance the reaction rate. [ABSTRACT FROM AUTHOR]

In recent years, the role of reactive oxygen species (ROS) in regulating cancer cell apoptosis, inflammation, cell ischemia, and cell signaling pathways has been well established. The most common sources of intracellular ROS are the mitochondrial electron transport system, NADH oxidase, and cytochrome P450. In this study, we investigated the dynamics and permeability of ROS using molecular dynamics (MD) simulations on native skin-lipid bilayer membranes. Native skin-lipid bilayers are composed of ceramide, cholesterol, and free fatty acid in an almost equal molar ratio (1:1:1). Dynamic distribution studies on ROS, i.e., hydrogen peroxide (H2O2) and O2 (1O2 by analogy), revealed that these species interact with cholesterol as a primary target in lipid peroxidation of the skin-lipid bilayer. Moreover, the permeability of ROS, i.e., H2O2, hydroxyl radicals (HO), hydroperoxy radical (HOO), and O2, along the skin-lipid bilayer was measured using free energy profiles (FEPs). The FEPs showed that in spite of high-energy barriers, ROS traveled through the membrane easily. Breaching the free energy barriers, these ROS permeated into the membrane, inflicting oxidative stress, and causing apoptosis. Collectively, the insight acquired from simulations may result in a better understanding of oxidative stress at the atomic level.

In recent years, the role of reactive oxygen species (ROS) in regulating cancer cell apoptosis, inflammation, cell ischemia, and cell signaling pathways has been well established. The most common sources of intracellular ROS are the mitochondrial electron transport system, NADH oxidase, and cytochrome P450. In this study, we investigated the dynamics and permeability of ROS using molecular dynamics (MD) simulations on native skin-lipid bilayer membranes. Native skin-lipid bilayers are composed of ceramide, cholesterol, and free fatty acid in an almost equal molar ratio (1:1:1). Dynamic distribution studies on ROS, i.e., hydrogen peroxide (H2O2) and O2 (1O2 by analogy), revealed that these species interact with cholesterol as a primary target in lipid peroxidation of the skin-lipid bilayer. Moreover, the permeability of ROS, i.e., H2O2, hydroxyl radicals (HO), hydroperoxy radical (HOO), and O2, along the skin-lipid bilayer was measured using free energy profiles (FEPs). The FEPs showed that in spite of high-energy barriers, ROS traveled through the membrane easily. Breaching the free energy barriers, these ROS permeated into the membrane, inflicting oxidative stress, and causing apoptosis. Collectively, the insight acquired from simulations may result in a better understanding of oxidative stress at the atomic level. [ABSTRACT FROM AUTHOR]

Despite its critical role in determining the performance of lithium ion batteries (LIBs), evolution of the chemical composition and morphology of the solid electrolyte interphase (SEI) formed on graphite negative electrodes remains poorly described even for a conventional electrolyte consisting of 1 M LiPF 6 dissolved in a mixture of ethylene carbonate (EC)/dimethyl carbonate (DMC), which is considered here. The EC − radical anion produced from one-electron reduction of EC is known to be a key intermediate responsible for the formation of two commonly found products in the SEI, carbonate (CO 3 2− ) and ethylene dicarbonate (EDC 2− ). We evaluate the diffusion behavior of EC − associated with solvent reorganization near the graphite electrode using molecular dynamics (MD) and metadynamics simulations. The predicted free energy profiles of EC − transport at the onset of SEI formation show two distinct minima, depending on the EC:DMC ratio of the solvent and the voltage applied to the electrode. EC − radical intermediates trapped in the free energy well located at z  = 0.65 nm (or z  = 1.5 nm) from the electrode surface may favorably undergo further reduction to CO 3 2− (or a combination reaction with another EC − to form EDC 2− ). Moreover, suppressed EC − migration could contribute to the formation of a thin, compact SEI layer. This study highlights that in addition to the kinetics and thermodynamics of solvent reduction, the near-electrode transport of reaction intermediates/products should be considered in modeling of SEI structure and growth. [ABSTRACT FROM AUTHOR]

The synergistic relationship between the proton conductive channel environment and the hydrated proton structure plays a decisive role in understanding the mechanism of proton transfer through proton exchange membrane. It is known that sulfonic acid group has a great contribution to the micro segregation in proton exchange membrane of fuel cell. This study employs classical molecular dynamics simulation to investigate the independent effect of sulfonic acid group on the formation of hydrogen bond network confined in the proton conductive channel. The inner wall of CNT is decorated with sulfonic acid groups and/or fluorine to analyze the independent impact of the factors. It is shown that the free energy barrier for hydronium ion exists around the sulfonic acid group. The electronic attraction of fluorine atoms lowers the free energy of hydronium ion in the channel, decreasing the binding energy of sulfonic group to proton. [ABSTRACT FROM AUTHOR]