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[Display omitted] Understanding the mechanisms of proton transfer on quartz surfaces in water is critical for a range of processes in geochemical, environmental, and materials sciences. The wide range of surface acidities (>9 p K a units) found on the ubiquitous mineral quartz is caused by the structural variations of surface silanol groups. Molecular scale simulations provide essential tools for elucidating the origin of site-specific surface acidities. We used density-functional tight-binding-based molecular dynamics combined with rare-event metadynamics simulations to probe the mechanisms of deprotonation reactions from ten representative surface silanol groups found on both pristine and defect-rich quartz (1 0 1) surfaces with Si vacancies. The results show that deprotonation is a highly dynamic process where both the surface hydroxyls and bridging oxygen atoms serve as the proton acceptors, in addition to water. Deprotonation of embedded silanols through intrasurface proton transfer exhibited lower p K a values with less H-bond participation and higher energy barriers, suggesting a new mechanism to explain the bimodal acidity observed on quartz surface. Defect sites, recently shown to comprise a significant portion of the quartz (1 0 1) surface, diversify the coordination and local H-bonding environments of the surface silanols, changing both the deprotonation pathways and energetics, leading to a wider range of p K a values (2.4 to 11.5) than that observed on pristine quartz surface (10.4 and 12.1). [ABSTRACT FROM AUTHOR]

Metadynamics electron microscopy metaInference (MEMMI) is an integrative structural biology method that enables a rapid and accurate characterization of protein structural dynamics at the atomic level and the error in the cryo‐EM experimental data, even in cases where conformations are separated by high energy barriers. It achieves this by incorporating (a) cryo‐electron microscopy electron density maps with (b) metadynamic‐enhanced‐sampling molecular dynamics. Here, I showcase the setup and analysis protocol of MEMMI, used to discover the atomistic structural ensemble and error in the cryo‐EM electron density map of the fuzzy coat of IAPP, a fibril implicated in type II diabetes. [ABSTRACT FROM AUTHOR]

Using density functional theory and metadynamics simulations with density functional tight-binding theory, we study cellobiose hydrolysis and glucose hydrogenation with SiO 2 -supported Pt and Pd catalysts in hot water, relevant to green cellulose conversion. We found that cellobiose can be hydrolyzed by hydrogen atom adsorbed on metal or proton spilled-over SiO 2 to form glucose. Glucose can then be hydrogenated by hydrogen atoms adsorbed at metal/water interface forming sorbitol. The reaction barriers of hydrolysis and hydrogenation at Pt/water interface are lower than at Pd/water interface, which explains an experimental finding that Pt performs better than Pd as a catalyst. [Display omitted] • Catalytic cellobiose hydrolysis and glucose hydrogenation were studied theoretically. • Density functional theory and metadynamics simulations were used. • Reaction pathways of SiO 2 -supported Pt and Pd catalysts were clarified. • Calculated free energy barriers explain catalytic efficiencies in experiments. • The results are expected to provide useful information for catalyst design. [ABSTRACT FROM AUTHOR]

In this study, the CVD process of carbonization of {111} silicone surface is simulated employing ab initio metadynamics at the temperature of 1423 K. The entire chain of reactions is discovered, including the formation of an initial SiC crystallite seed with three carbon atoms, in the presence of native oxide. The characterization of all mechanisms includes transition states (TSs) and intermediate products. The forward free energy barriers were measured when possible. Carbonization always begins with alkylated surface products and progresses through loss of hydrogen. Only when all hydrogen atoms are lost, the carbon is accommodated in the crystal volume. Oxygen atoms of the native oxide may stay trapped in the SiC phase or in a buffer Si–C–O phase, forming a glass layer there. The native oxygen expresses certain mobility at the surface of the material. Occasionally TSs with hypervalent carbon and silicon atoms occur. The rate-determining reaction in the CVD synthesis of SiC has a free energy barrier of 173 kJ/mol. [Display omitted] • SiC growth by carbonization of {111} Si is simulated by ab initio metadynamics. • Reaction pathways even up to the formation of 3-membered SiC seed were studied. • The transition states and intermediate products are characterized. • The carbon is accommodated in the crystal lattice when all H-atoms are lost. • O-atoms may stay trapped in the SiC phase or in a buffer Si–C–O phase. [ABSTRACT FROM AUTHOR]

Inverse electron demand [4+2] Diels–Alder (iEDDA) reactions as well as unprecedented nucleophilic (azaphilic) additions of R-substituted silyl-enol ethers (where R is Phenyl, Methyl, and Hydrogen) to 1,2,4,5-tetrazine (s-tetrazine) catalyzed by BF 3 have recently been discovered (Simon et al. in Org Lett 23(7):2426–2430, 2021), where static calculations were employed for calculation of activation energies. In order to have a more realistic dynamic description of these reactions in explicit solution at ambient conditions, in this work we use a semiempirical tight-binding method combined with enhanced sampling techniques to calculate free energy surfaces (FESs) of the iEDDA and azaphilic addition reactions. Relevant products of not only s-tetrazine but also its derivatives such as BF 3 -mediated s-tetrazine adducts are investigated. We reconstruct the FESs of the iEDDA and azaphilic addition reactions using metadynamics and blue moon ensemble, and compare the ability of different collective variables (CVs) including bond distances, Social PeRmutation INvarianT (SPRINT) coordinates, and path-CV to describe the reaction pathway. We find that when a bulky Phenyl is used as a substituent at the dienophile the azaphilic addition is preferred over the iEDDA reaction. In addition, we also investigate the effect of BF 3 in the diene and steric hindrance in the dienophile on the competition between the iEDDA and azaphilic addition reactions, providing chemical insight for reaction design. [ABSTRACT FROM AUTHOR]

Sugar alcohol dehydration in hot water is an important reaction that allows for environmentally friendly biomass conversion without the use of organic solvents. Here, we report a free‐energy analysis by metadynamics (MTD) simulations based on ab initio density functional theory and semiempirical density‐functional tight‐binding method to understand the mechanism of dehydration reactions of d‐sorbitol (SBT) in hot acidic water. Comparing the results of ab initio and semiempirical MTD, it was found that the latter gives a reliable free energy surface of SBT dehydration reaction, although the results vary upon the inclusion of dispersion correction. It was found that the reaction proceeds consistently via an SN2 mechanism, whereby the free energy of protonation of the hydroxyl group created as an intermediate is affected by the acidic species. This mechanism was further verified by real‐time trajectories started from the transition state using ab initio molecular dynamics simulations. The free energy barriers of the reaction pathways leading to five‐membered ether products are lower than those leading to six‐membered ether products, in agreement with experiment. This outcome can be ascribed, in part, to our finding that the reaction barrier of the pathway is correlated to the stability of the SBT confined conformation at the initial stage of the reaction. [ABSTRACT FROM AUTHOR]

SUCNR1 is an auto- and paracrine sensor of the metabolic stress signal succinate. Using unsupervised molecular dynamics (MD) simulations (170.400 ns) and mutagenesis across human, mouse, and rat SUCNR1, we characterize how a five-arginine motif around the extracellular pole of TM-VI determines the initial capture of succinate in the extracellular vestibule (ECV) to either stay or move down to the orthosteric site. Metadynamics demonstrate low-energy succinate binding in both sites, with an energy barrier corresponding to an intermediate stage during which succinate, with an associated water cluster, unlocks the hydrogen-bond-stabilized conformationally constrained extracellular loop (ECL)-2b. Importantly, simultaneous binding of two succinate molecules through either a "sequential" or "bypassing" mode is a frequent endpoint. The mono-carboxylate NF-56-EJ40 antagonist enters SUCNR1 between TM-I and -II and does not unlock ECL-2b. It is proposed that occupancy of both high-affinity sites is required for selective activation of SUCNR1 by high local succinate concentrations. [Display omitted] • SUCNR1 attracts and binds succinate through a cluster of arginines around TM-VI • The arginines constitute two low-energy succinate binding sites • SUCNR1 is activated by simultaneous binding of two succinates at high concentrations • Binding of succinate, but not antagonist, unlocks constrained ECL-2 via water cluster Extracellular succinate is an auto- and paracrine metabolic stress signal sensed by SUCNR1. Using MD simulations, Shenol et al. found that SUCNR1 has two low-energy binding sites, and its selective activation by high, local concentrations of succinate requires simultaneous occupancy of both high-affinity sites. [ABSTRACT FROM AUTHOR]

The folded form of S‐Peptide is found to be essential for the activation of RNase‐S complex. Herein the folding‐unfolding dynamics of S‐Peptide and its protonated form in mild acidic conditions are investigated to assess the most favorable folding pathway in physiological conditions. Our results confirm that the pH assisted S‐peptide structures could indeed influence on the binding and collapse of the hydrophobic groups, which in turn can modulate the structural stability of S‐Peptide α‐helix. We affirm that the protonated S‐Peptide has its partially and completely folded states which are readily accessible whereas in the case of non‐protonated S‐Peptide, there exists an energy barrier in attaining the folds. Further, the RNase‐S complex formation could be mostly assisted by mild acidic pH and we also confirm that the folding‐unfolding pathways of S‐Peptide are independent of the pH. [ABSTRACT FROM AUTHOR]

The recently discovered anti-perovskites of the formula, Li 3 OCl 1 − x Br x , where x = 0 to 1 , have been garnering interest as potential candidates for solid electrolytes in battery applications. It is observed that the Li ion transport in these solids is rather slow, and unaccessible within typical molecular dynamics time scales. However, by judicially augmenting it with the accelerated sampling technique of metadynamics, the present study derives fresh insights on the nature of Li ion transport in these systems. The microscopic of ion migration along intra- and inter-octahedral channels, suggests that intra-octahedral channels account for over 95% Li transport in the system. The bromide end member offers lower free energy barriers, due to entropic factors resulting from the expansion of the lattice. However, the large free energy barriers estimated in the present work suggest that the undoped Li 3 OCl 1 − x Br x anti-perovskites are unlikely to exhibit superionic behavior. [Display omitted] [ABSTRACT FROM AUTHOR]

Valinomycin is a potent ionophore known for its ability to transport potassium ions across biological membranes. The study focuses on the hydroxylated analogues of valinomycin (HyVLMs) and compares their energy profiles and capabilities for transporting potassium ions across phospholipid membranes. Using metadynamics, we investigated the energy profiles of wild type valinomycin (VLM_1) and its three hydroxylated analogues (VLM_2, VLM_3, and VLM_4). We observed that all analogues exhibited energy maxima in the centre of the membrane and preferred positions below the phospholipid heads. Furthermore, the entry barriers for membrane penetration were similar among the analogues, suggesting that the hydroxyl group did not significantly affect their passage through the membrane. Transition state calculations provided insights into the ability of valinomycin analogues to capture potassium ions, with VLM_4 showing the lowest activation energy and VLM_2 displaying the highest. Our findings contribute to understanding the mechanisms of potassium transport by valinomycin analogues and highlight their potential as ionophores. The presence of the hydroxyl group is of particular importance because it paves the way for subsequent chemical modifications and the synthesis of new antiviral agents with reduced intrinsic toxicity. [Display omitted] • Hydroxylated analogues of valinomycin (VLM_2, VLM_3, and VLM_4) were evaluated for their energy profile. • Valinomycins exhibit energy maxima in the membrane, with a preferred position below the phospholipid heads. • Hydroxylated analogues VLMK_3 and VLMK_4 display similar energy profiles and potential for efficient potassium ion binding. • Analogue VLMK_2 shows the difficulty in recovering K+ ions and crossing the membrane. • The hydroxyl group in VLMK_3 and VLMK_4 facilitates potassium complexation and offers versatile chemical modifications. [ABSTRACT FROM AUTHOR]

Free energy surfaces associated to the adsorption of metal cations (, , , and ) in biological environments have been computed by metadynamics simulations. In all cases, the systems were modelled using the CHARMM36 force field. The free-energy landscapes unveil specific binding behaviour of metal cations. So, and are more likely to stay in the aqueous solution, and can easily bind to a few lipid oxygens by overcoming low free-energy barriers. Differently, is most stable when bound to four lipid oxygens of the membranes, rather than being hydrated in the aqueous solution. Finally, is tightly hydrated, and can hardly lose a hydration water and bind directly to the membranes. When cholesterol is included inside the membrane at concentration up to 50%, the resulting free-energy landscapes reveal the competition between binding of sodium to water and to lipid head groups, although the binding competitiveness of lipid head groups is diminished by cholesterol contents. When cholesterol concentration is greater than 30%, the ionic binding is significantly reduced, which coincides with the phase transition point of DMPC-cholesterol membranes from a liquid-disordered phase to a liquid-ordered phase. [ABSTRACT FROM AUTHOR]

We present the reactivity of an organic intermediate by studying the proton transfer process from water to ketyl radical anion using gas phase electronic structure calculations and the metadynamics method based first principles molecular dynamics (FPMD) simulations. Our results indicate that during the micro solvation of anion by water molecules systematically, the presence of minimum three water molecules in the gas phase cluster is sufficient to observe the proton transfer event. The analysis of trajectories obtained from initial FPMD simulation of an aqueous solution of the anion does not show any evident of complete transfer of the proton from water. The cooperativity of water molecules and the relatively weak anion-water interaction in liquid state prohibit the full release of the proton. Using biasing potential through first principles metadynamics simulations, we report the observation of proton transfer reaction from water to ketyl radical anion with a barrier height of 16.0 kJ/mol. [ABSTRACT FROM AUTHOR]

Background Molecular dynamics has emerged as an important research methodology covering systems to the level of millions of atoms. However, insufficient sampling often limits its application. The limitation is due to rough energy landscapes, with many local minima separated by high-energy barriers, which govern the biomolecular motion. Scope of review In the past few decades methods have been developed that address the sampling problem, such as replica-exchange molecular dynamics, metadynamics and simulated annealing. Here we present an overview over theses sampling methods in an attempt to shed light on which should be selected depending on the type of system property studied. Major conclusions Enhanced sampling methods have been employed for a broad range of biological systems and the choice of a suitable method is connected to biological and physical characteristics of the system, in particular system size. While metadynamics and replica-exchange molecular dynamics are the most adopted sampling methods to study biomolecular dynamics, simulated annealing is well suited to characterize very flexible systems. The use of annealing methods for a long time was restricted to simulation of small proteins; however, a variant of the method, generalized simulated annealing, can be employed at a relatively low computational cost to large macromolecular complexes. General significance Molecular dynamics trajectories frequently do not reach all relevant conformational substates, for example those connected with biological function, a problem that can be addressed by employing enhanced sampling algorithms. This article is part of a Special Issue entitled Recent developments of molecular dynamics. [ABSTRACT FROM AUTHOR]

Metadynamics (MetaD) is a method that augments molecular dynamics (MD) calculations of all types (classical and quantum) to help systems overcome energy barriers and explore regions of phase space that would otherwise not be seen during a simulation. The method has seen wide ranging uses, and it has proven especially useful for the study of reactions in which bonds break and form. In such cases, the timescale challenges of MD are profoundly limiting, and the advent of this new paradigm for biasing simulations has proven to be incredibly useful. In this review, we set out to summarise the large body of work that uses MetaD for studying reactions so that others can more easily implement this method in their own work. After a brief introduction of the method, we provide detailed summaries of the method applied in various contexts including condensed phase and biological reactions. [ABSTRACT FROM AUTHOR]

Metadynamics is a popular enhanced sampling method based on the recurrent application of a history-dependent adaptive bias potential that is a function of a selected number of appropriately chosen collective variables. In this work, using metadynamics simulations, we performed a computational study for the diffusion of vacancies on three different Al surfaces [reconstructed Al(100), Al(110), and Al(111) surfaces]. We explored the free energy landscape of diffusion and estimated the barriers associated with this process on each surface. It is found that the surfaces are unique regarding vacancy diffusion. More specically, the reconstructed Al(110) surface presents four metastable states on the free energy surface having sizable and connected passage-ways with an energy barrier of height 0.55 eV. On the other hand, the reconstructed Al(100)/Al(111) surfaces exhibit two/three metastable states, respectively, with an energy barrier of height 0.33 eV. The findings in this study can help to understand surface vacancy diffusion in technologically relevant Al surfaces. [ABSTRACT FROM AUTHOR]