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For a detailed understanding of chemical processes in nature and industry, we need accurate models of chemical reactions in complex environments. While Eyring transition state theory is commonly used for modeling chemical reactions, it is most accurate for small molecules in the gas phase. A wide range of alternative rate theories exist that can better capture reactions involving complex molecules and environmental effects. However, they require that the chemical reaction is sampled by molecular dynamics simulations. This is a formidable challenge since the accessible simulation timescales are many orders of magnitude smaller than typical timescales of chemical reactions. To overcome these limitations, rare event methods involving enhanced molecular dynamics sampling are employed. In this work, thermal isomerization of retinal is studied using tight‐binding density functional theory. Results from transition state theory are compared to those obtained from enhanced sampling. Rates obtained from dynamical reweighting using infrequent metadynamics simulations were in close agreement with those from transition state theory. Meanwhile, rates obtained from application of Kramers' rate equation to a sampled free energy profile along a torsional dihedral reaction coordinate were found to be up to three orders of magnitude higher. This discrepancy raises concerns about applying rate methods to one‐dimensional reaction coordinates in chemical reactions. [ABSTRACT FROM AUTHOR]

The oligomeric ruthenium‐based water oxidation catalyst, Ru(bda), is known to be experimentally anchored on graphitic surfaces through CH‐π stacking interactions between the auxiliary bda ([2,2′‐bipyridine]‐6,6′‐dicarboxylate) ligand bonded to ruthenium and the hexagonal rings of the surface. This anchoring provides control over their molecular coverage and enables efficient catalysis of water oxidation to dioxygen. The oligomeric nature of the molecule offers multiple anchoring sites at the surface, greatly enhancing the overall stability of the hybrid catalyst‐graphitic surface anode through dynamic bonding. However, the impact of this dynamic anchoring on the overall catalytic mechanism is still a topic of debate. In this study, a crucial proton‐coupled electron transfer event in the catalytic cycle is investigated using DFT‐based molecular dynamics simulations plus metadynamics. The CH‐π stacking anchoring plays a critical role not only in stabilizing this hybrid system but also in facilitating the proton‐coupled electron transfer event with possible vibronic couplings between the anchoring bonds motion and charge fluctuations at the catalyst – graphitic surface interface. Furthermore, this computational investigation displays the presence of a quartet spin state intermediate that can lead to the experimentally observed and thermodynamically more stable doublet spin state. [ABSTRACT FROM AUTHOR]

[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]

The amino acid substitutions in Klebsiella pneumoniae carbapenemase 2 (KPC‐2) that have arisen in the clinic are observed to lead to the development of resistance to ceftazidime‐avibactam, a preferred treatment for KPC bearing Gram‐negative bacteria. Specific substitutions in the omega loop (R164‐D179) result in changes in the structure and function of the enzyme, leading to alterations in substrate specificity, decreased stability, and more recently observed, increased resistance to ceftazidime/avibactam. Using accelerated rare‐event sampling well‐tempered metadynamics simulations, we explored in detail the structural role of R164 and D179 variants that are described to confer ceftazidime/avibactam resistance. The buried conformation of D179 substitutions produce a pronounced structural disorder in the omega loop ‐ more than R164 mutants, where the crystallographic omega loop structure remains mostly intact. Our findings also reveal that the conformation of N170 plays an underappreciated role impacting drug binding and restricting deacylation. The results further support the hypothesis that KPC‐2 D179 variants employ substrate‐assisted catalysis for ceftazidime hydrolysis, involving the ring amine of the aminothiazole group to promote deacylation and catalytic turnover. Moreover, the shift in the WT conformation of N170 contributes to reduced deacylation and an altered spectrum of enzymatic activity. [ABSTRACT FROM AUTHOR]

The amino acid substitutions in Klebsiella pneumoniae carbapenemase 2 (KPC‐2) that have arisen in the clinic are observed to lead to the development of resistance to ceftazidime‐avibactam, a preferred treatment for KPC bearing Gram‐negative bacteria. Specific substitutions in the omega loop (R164‐D179) result in changes in the structure and function of the enzyme, leading to alterations in substrate specificity, decreased stability, and more recently observed, increased resistance to ceftazidime/avibactam. Using accelerated rare‐event sampling well‐tempered metadynamics simulations, we explored in detail the structural role of R164 and D179 variants that are described to confer ceftazidime/avibactam resistance. The buried conformation of D179 substitutions produce a pronounced structural disorder in the omega loop ‐ more than R164 mutants, where the crystallographic omega loop structure remains mostly intact. Our findings also reveal that the conformation of N170 plays an underappreciated role impacting drug binding and restricting deacylation. The results further support the hypothesis that KPC‐2 D179 variants employ substrate‐assisted catalysis for ceftazidime hydrolysis, involving the ring amine of the aminothiazole group to promote deacylation and catalytic turnover. Moreover, the shift in the WT conformation of N170 contributes to reduced deacylation and an altered spectrum of enzymatic activity. [ABSTRACT FROM AUTHOR]

Sampling rare events in metastable dynamical systems is often a computationally expensive task and one needs to resort to enhanced sampling methods such as importance sampling. Since we can formulate the problem of finding optimal importance sampling controls as a stochastic optimization problem, this then brings additional numerical challenges and the convergence of corresponding algorithms might suffer from metastabilty. In this article, we address this issue by combining systematic control approaches with the heuristic adaptive metadynamics method. Crucially, we approximate the importance sampling control by a neural network, which makes the algorithm in principle feasible for high-dimensional applications. We can numerically demonstrate in relevant metastable problems that our algorithm is more effective than previous attempts and that only the combination of the two approaches leads to a satisfying convergence and therefore to an efficient sampling in certain metastable settings. [ABSTRACT FROM AUTHOR]

Cosolvent molecular dynamics (MD) simulations are molecular dynamics simulations used to identify preferable locations of small organic fragments on a protein target. Most cosolvent molecular dynamics workflows make use of only water-soluble fragments, as hydrophobic fragments would cause lipophilic aggregation. To date the two approaches that allow usage of hydrophobic cosolvent molecules are to use a low (0.2 M) concentration of hydrophobic probes, with the disadvantage of a lower sampling speed, or to use force field modifications, with the disadvantage of a difficult and inflexible setup procedure. Here we present a third alternative, that does not suffer from low sampling speed nor from cumbersome preparation procedures. We have built an easy-to-use open source command line tool PART (Plumed Automatic Restraining Tool) to generate a PLUMED file handling all intermolecular restraints to prevent lipophilic aggregation. We have compared restrained and unrestrained cosolvent MD simulations, showing that restraints are necessary to prevent lipophilic aggregation at hydrophobic probe concentrations of 0.5 M. Furthermore, we benchmarked PART generated restraints on a test set of four proteins (Factor-Xa, HIV protease, P38 MAP kinase and RNase A), showing that cosolvent MD with PART generated restraints qualitatively reproduces binding features of cocrystallised ligands. [ABSTRACT FROM AUTHOR]

We present here a joint experimental and computational study on the formation of benzothiazoles. Our investigation reveals a green protocol for accessing benzothiazoles from acyl chlorides using either water alongside a reducing agent as the reaction medium or in combination with stoichiometric amounts of a weak acid, instead of the harsh conditions and catalysts previously reported. Specifically, we show that a protic solvent, particularly water, enables the formation of 2‐substituted benzothiazoles from N‐acyl 1,2‐aminothiophenols already at room temperature, without the need for strong acids or metal catalysts. DFT Molecular Dynamics simulations coupled with advanced enhanced sampling techniques provide a clear understanding of the catalytic role of water. We demonstrate how bulk water – due to its extended network of hydrogen bonds and an efficient Grotthuss mechanism – provides a reaction path that strongly reduces the reaction barriers compared to aprotic environments, namely more than 80 kJ/mol for the first reaction step and 250 kJ/mol for the second. Finally, we discuss the influence of different aliphatic and aromatic substituents with varying electronic properties on chemical reactivity. Besides providing in‐depth mechanistic insights, we believe that our findings pave the way for a greener route toward an important class of bioactive molecules. [ABSTRACT FROM AUTHOR]

Enediyne antibiotics are a class of potent DNA-cleaving antitumor agents. Searching for promising analogs of enediyne antibiotics, the features of interaction with the DNA of enediynes fused with heterocycles have been studied using molecular modeling methods. Depending on their structure, 10-membered heteroenediynes can exhibit both intercalator properties and bind to the minor groove of DNA. Variation of the heterocyclic part annulated with the enediyne cycle as well as the attachment of substituents at the enediyne core makes it possible to change the DNA method of binding mode, from intercalation to minor groove-binding. [ABSTRACT FROM AUTHOR]

Stochastic systems often exhibit multiple viable metastable states that are long-lived. Over very long timescales, fluctuations may push the system to transition between them, drastically changing its macroscopic configuration. In realistic systems, these transitions can happen via multiple physical mechanisms, corresponding to multiple distinct transition channels for a pair of states. In this paper, we use the fact that the transition path ensemble is equivalent to the invariant measure of a gradient flow in pathspace, which can be efficiently sampled via metadynamics. We demonstrate how this pathspace metadynamics, previously restricted to reversible molecular dynamics, is in fact very generally applicable to metastable stochastic systems, including irreversible and time-dependent ones, and allows rigorous estimation of the relative probability of competing transition paths. We showcase this approach on the study of a stochastic partial differential equation describing magnetic field reversal in the presence of advection. [ABSTRACT FROM AUTHOR]

Human leishmaniasis is a neglected tropical disease which affects nearly 1.5 million people every year, with Mexico being an important endemic region. One of the major defense mechanisms of these parasites is based in the polyamine metabolic pathway, as it provides the necessary compounds for its survival. Among the enzymes in this route, trypanothione reductase (TryR), an oxidoreductase enzyme, is crucial for the Leishmania genus' survival against oxidative stress. Thus, it poses as an attractive drug target, yet due to the size and features of its catalytic pocket, modeling techniques such as molecular docking focusing on that region is not convenient. Herein, we present a computational study using several structure-based approaches to assess the druggability of TryR from L. mexicana, the predominant Leishmania species in Mexico, beyond its catalytic site. Using this consensus methodology, three relevant pockets were found, of which the one we call σ-site promises to be the most favorable one. These findings may help the design of new drugs of trypanothione-related diseases. [ABSTRACT FROM AUTHOR]

In the context of drug discovery, computational methods were able to accelerate the challenging process of designing and optimizing a new drug candidate. Amongst the possible atomistic simulation approaches, metadynamics (metaD) has proven very powerful. However, the choice of collective variables (CVs) is not trivial for complex systems. To automate the process of CVs identification, two different machine learning algorithms were applied in this study, namely DeepLDA and Autoencoder, to the metaD simulation of a well‐researched drug/target complex, consisting in a pharmacologically relevant non‐canonical DNA secondary structure (G‐quadruplex) and a metallodrug acting as its stabilizer, as well as solvent molecules. [ABSTRACT FROM AUTHOR]

Car–Parrinello molecular dynamics and metadynamics were carried out for salt-free Wittig reaction of non-stabilized, semi-stabilized and stabilized ylides and correlated to static quantum calculation at PBE/6-31G(d, p), including continuum solvation. The Grimme's dispersion correction approach (DFT-D) was employed throughout the study for both methods. The aim of the present investigations is to reformulate in details than has been possible hitherto, the reaction path and introduce all the stable and metastable states in the Wittig reaction, using ab-initio molecular dynamics tools. In what follows, we show that in the calculated free energy surface, betaine appears at the beginning of the reaction followed by oxaphosphetane for all ylides. The betaine has a higher energy and short life time than oxaphosphetane. It is found that increasing the ylide stability extends the reaction onset time and reduces the overall reaction time. The metadynamics trajectory (metatrajectory) shows the early formation of the C–C bond followed by the P–O bonding formation and simultaneous breaking of the P–C and C–O bond. Within this process, a high E selectivity for all ylides is observed. The metadynamics analysis encompasses all possible energy reaction coordinates; this property provides a more detailed mechanistic picture. Comparison with static calculations demonstrates the potential of the metadynamics approach in the conformational and geometric analysis of the cycloaddition and the cycloelimination processes. [ABSTRACT FROM AUTHOR]

Here, we present a parametrization of the metadynamics simulations for reactions involving breaking the chemical bonds along a single collective variable coordinate. The parameterization is based on the similarity between the bias potential in metadynamics and the quantum potential in the de Broglie–Bohm formalism. We derive the method and test it on two prototypical reaction types: proton transfer and breaking of the cyclohexene cycle (reversed Diels–Alder reaction). [ABSTRACT FROM AUTHOR]

The results are presented of a theoretical study on assessment of the stereoselectivity of processes aimed at increasing the enantiomeric excess of chiral pyrimidinones, products of the Biginelli reaction. The effects of hydroxyproline-containing podands used as chiral inductors, viz., the influence of the base or salt forms and of the oxyethylene chain length in the stage of formation of iminium intermediates of the Biginelli reaction are considered. A methodology is proposed for modeling a multicomponent reaction mixture by the molecular dynamics method. The strategy proved itself in quantitative assessment of the stereoselectivity of the approach of urea molecule to the iminium stereoisomers under the conditions of a simulated diffusion stage of the reaction. The energy maps constructed in the polar coordinates make it possible to visually assess the preference of the reagent approach to the different diastereotopic sides. [ABSTRACT FROM AUTHOR]

Soil bacteria can produce urease, which catalyzes the hydrolysis of urea to ammonia (NH3) and carbamate. A variety of urease inhibitors have been proposed to reduce NH3 volatilization by interfering with the urease activity. We report a quantum mechanics/molecular mechanics molecular dynamics (QM/MM MD) study on the mechanism employed for the inhibition of urease by three representative competitive inhibitors; namely, acetohydroxamic acid (AHA), hydroxyurea (HU), and N-(n-butyl)phosphorictriamide (NBPTO). The possible connections between the structural and thermodynamical properties and the experimentally observed inhibition efficiency were evaluated and characterized. We demonstrate that the binding affinity decreases in the order NBPTO >> AHA > HU in terms of the computed activation and reaction free energies. This trend also indicates that NBPTO shows the highest inhibitory activity and the lowest IC50 value of 2.1 nM, followed by AHA (42 μM) and HU (100 μM). It was also found that the X=O moiety (X = carbon or phosphorous) plays a crucial role in the inhibitor binding process. These findings not only elucidate why the potent urease inhibitors are effective but also have implications for the design of new inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] Exploring the free energy surface of the R–NHC coupling reaction in the key intermediates of the Mizoroki–Heck and cross-coupling catalytic cycles has been conducted by the methods of biased and unbiased molecular dynamics. Molecular dynamics simulations were carried out both in vacuum and in a polar solvent, with the following main observations on the influence of the media: (1) the solvent prevents the dissociation of the solvate ligand, so the R–NHC coupling proceeds in a four-coordination complex (rather than in a three-coordination one, as in the case of a gas-phase reaction); (2) in the condensed phase, the potential barrier of the reaction is significantly higher compared to the same process in vacuum (17.7 vs. 21.8 kcal mol-1); (3) polar solvent stabilizes the R–NHC coupling product. The reaction in a polar medium is exergonic (Δ G = −3.9 kcal mol-1), in contrast to the in vacuum modeling, where the process is endergonic (Δ G = 0.4 kcal mol-1). [ABSTRACT FROM AUTHOR]

The development of potent non-nucleoside inhibitors (NNIs) could be an alternate strategy to combating infectious bovine viral diarrhea virus (BVDV), other than the traditional vaccination. RNA-dependent RNA polymerase (RdRp) is an essential enzyme for viral replication; therefore, it is one of the primary targets for countermeasures against infectious diseases. The reported NNIs, belonging to the classes of quinolines (2h: imidazo[4,5-g]quinolines and 5m: pyrido[2,3-g] quinoxalines), displayed activity in cell-based and enzyme-based assays. Nevertheless, the RdRp binding site and microscopic mechanistic action are still elusive, and can be explored at a molecular level. Here, we employed a varied computational arsenal, including conventional and accelerated methods, to identify quinoline compounds' most likely binding sites. Our study revealed A392 and I261 as the mutations that can render RdRp resistant against quinoline compounds. In particular, for ligand 2h, mutation of A392E is the most probable mutation. The loop L1 and linker of the fingertip is recognized as a pivotal structural determinant for the stability and escape of quinoline compounds. Overall, this work demonstrates that the quinoline inhibitors bind at the template entrance channel, which is governed by conformational dynamics of interactions with loops and linker residues, and reveals structural and mechanistic insights into inhibition phenomena, for the discovery of improved antivirals. [ABSTRACT FROM AUTHOR]

Metadynamics calculations of large chemical systems with ab initio methods are computationally prohibitive due to the extensive sampling required to simulate the large degrees of freedom in these systems. To address this computational bottleneck, we utilized a GPU-enhanced density functional tight binding (DFTB) approach on a massively parallelized cloud computing platform to efficiently calculate the thermodynamics and metadynamics of biochemical systems. To first validate our approach, we calculated the free-energy surfaces of alanine dipeptide and showed that our GPU-enhanced DFTB calculations qualitatively agree with computationally-intensive hybrid DFT benchmarks, whereas classical force fields give significant errors. Most importantly, we show that our GPU-accelerated DFTB calculations are significantly faster than previous approaches by up to two orders of magnitude. To further extend our GPU-enhanced DFTB approach, we also carried out a 10 ns metadynamics simulation of remdesivir, which is prohibitively out of reach for routine DFT-based metadynamics calculations. We find that the free-energy surfaces of remdesivir obtained from DFTB and classical force fields differ significantly, where the latter overestimates the internal energy contribution of high free-energy states. Taken together, our benchmark tests, analyses, and extensions to large biochemical systems highlight the use of GPU-enhanced DFTB simulations for efficiently predicting the free-energy surfaces/thermodynamics of large biochemical systems. [ABSTRACT FROM AUTHOR]

Closo‐carborane anions are prominent, whereas the cations of the same are less abundant in the literature. As these ions have similar size and are weakly coordinating, the ionic liquids of these two ions could have important applications in many areas of chemistry. In view of limited number of polyhedral carborane cations available, we revisited the rearrangement of dicarboranyl methyl cation (7‐CH2 7,9‐nido‐C2B9H10+) using ab initio molecular dynamics calculations with metadynamics. Our simulations confirmed the concerted mechanism of the rearrangement. We believe this work will resume the interest in its synthesis and carborane cations in general. [ABSTRACT FROM AUTHOR]

The nature of intra- and intermolecular non-covalent interactions was studied in four naphthalene derivatives commonly referred to as "proton sponges". Special attention was paid to an intramolecular hydrogen bond present in the protonated form of the compounds. The unsubstituted "proton sponge" served as a reference structure to study the substituent influence on the hydrogen bond (HB) properties. We selected three compounds substituted by methoxy, amino, and nitro groups. The presence of the substituents either retained the parent symmetry or rendered the compounds asymmetric. In order to reveal the non-covalent interaction properties, the Hirshfeld surface (HS) was computed for the crystal structures of the studied compounds. Next, quantum-chemical simulations were performed in vacuo and in the crystalline phase. Car–Parrinello molecular dynamics (CPMD), Path Integral Molecular Dynamics (PIMD), and metadynamics were employed to investigate the time-evolution changes of metric parameters and free energy profile in both phases. Additionally, for selected snapshots obtained from the CPMD trajectories, non-covalent interactions and electronic structure were studied. Quantum theory of atoms in molecules (QTAIM) and the Density Overlap Regions Indicator (DORI) were applied for this purpose. It was found based on Hirshfeld surfaces that, besides intramolecular hydrogen bonds, other non-covalent interactions are present and have a strong impact on the crystal structure organization. The CPMD results obtained in both phases showed frequent proton transfer phenomena. The proton was strongly delocalized in the applied time-scale and temperature, especially in the PIMD framework. The use of metadynamics allowed for tracing the free energy profiles and confirming that the hydrogen bonds present in "proton sponges" are Low-Barrier Hydrogen Bonds (LBHBs). The electronic and topological analysis quantitatively described the temperature dependence and time-evolution changes of the electronic structure. The covalency of the hydrogen bonds was estimated based on QTAIM analysis. It was found that strong hydrogen bonds show greater covalency, which is additionally determined by the proton position in the hydrogen bridge. [ABSTRACT FROM AUTHOR]

Small molecule antagonists that bind to the ligand-binding domain (LBD) of estrogen receptor alpha (ERα) are effective in treating ERα-positive breast cancer patients. However, acquired treatment resistance is observed in the presence of somatic mutations in LBD of ERα. Y537S is the most aggressive mutation, causing constitutive activity of ERα in the absence of ligand and reducing the affinity and sensitivity of certain antagonists such as 4-hydroxy tamoxifen (4-OHT). To better understand the mechanism of resistance to 4-OHT, we performed a comparative study of wild-type and Y537S mutant ERα in complex with 4-OHT using classical molecular dynamics and metadynamics. The results of this study indicated that Helix 12 (H12) disruption is a typical allosteric effect of 4-OHT, allowing the receptor to maintain an antagonistic conformation. The Y537S mutation induces the loss of this effect by stabilising H12 through the newly formed H-bond between E380 and S537, thereby strengthening H12 to adopt an agonistic conformation even when 4-OHT is bound. The obtained results and the approaches applied in this study could be used as proof of principle for discovering more potent ERα inhibitors to overcome the endocrine resistance. [ABSTRACT FROM AUTHOR]

The complex physics of glass-forming systems is controlled by the structure of the lowenergy portions of their potential energy landscapes. Here we report that a modified metadynamics algorithm efficiently explores and samples low-energy regions of such high-dimensional landscapes. In the energy landscape for a model foam, our algorithm finds and descends meandering canyons in the landscape, which contain dense clusters of energy minima along their floors. Similar canyon structures in the energy landscapes of two model glass formers--hard sphere fluids and the Kob-Andersen glass--allow us to reach high densities and low energies, respectively. In the hard sphere system, fluid configurations are found to form continuous regions that cover the canyon floors up to densities well above the jamming transition. For the Kob-Andersen glass former, our technique samples low-energy states with modest computational effort, with the lowest energies found approaching the predicted Kauzmann limit. [ABSTRACT FROM AUTHOR]

The World Health Organization has put drug resistance in tuberculosis on its list of significant threats, with a critical emphasis on resolving the genetic differences in Mycobacterium tuberculosis. This provides an opportunity for a better understanding of the evolutionary progression leading to anti-microbial resistance. Anti-microbial resistance has a great impact on the economic stability of the global healthcare sector. We performed a timeline genomic analysis from 2003 to 2021 of 578 mycobacterium genomes to understand the pattern underlying genomic variations. Potential drug targets based on functional annotation was subjected to pharmacophore-based screening of FDA-approved phyto-actives. Reaction search, MD simulations, and metadynamics studies were performed. A total of 4,76,063 mutations with a transition/transversion ratio of 0.448 was observed. The top 10 proteins with the least number of mutations were high-confidence drug targets. Aminoglycoside 2′-N-acetyltransferase protein (AAC2′), conferring resistance to aminoglycosides, was shortlisted as a potential drug target based on its function and role in bait drug synergism. Gentamicin-AAC2′ binding pose was used as a pharmacophore template to screen 10,570 phyto-actives. A total of 66 potential hits were docked to obtain naloxone as a lead—active with a docking score of −6.317. Naloxone is an FDA-approved drug that rapidly reverses opioid overdose. This is a classic case of a repurposed phyto-active. Naloxone consists of an amine group, but the addition of the acetyl group is unfavorable, with a reaction energy of 612.248 kcal/mol. With gentamicin as a positive control, molecular dynamic simulation studies were performed for 200 ns to check the stability of binding. Metadynamics-based studies were carried out to compare unbinding energy with gentamicin. The unbinding energies were found to be −68 and −74 kcal/mol for naloxone and gentamycin, respectively. This study identifies naloxone as a potential drug candidate for a bait drug synergistic approach against Mycobacterium tuberculosis. [ABSTRACT FROM AUTHOR]

A major concern in the modern cement industry is considering how to minimize the CO2 footprint. Thus, cements based on belite, an impure clinker mineral (CaO)2SiO2 (C2S in cement chemistry notation), which forms at lower temperatures, is a promising solution to develop eco-efficient and sustainable cement-based materials, used in enormous quantities. The slow reactivity of belite plays a critical role, but the dissolution mechanisms and kinetic rates at the atomistic scale are not known completely yet. This work aims to understand the dissolution behavior of different facets of β-C2S providing missing input data and an upscaling modeling approach to connect the atomistic scale to the sub-micro scale. First, a combined ReaxFF and metadynamics-based molecular dynamic approach are applied to compute the atomistic forward reaction rates (RD) of calcium (Ca) and silicate species of (100) facet of β-C2S considering the influence of crystal facets and crystal defects. To minimize the huge number of atomistic events possibilities, a generalized approach is proposed, based on the systematic removal of nearest neighbors' crystal sites. This enables us to tabulate data on the forward reaction rates of most important atomistic scenarios, which are needed as input parameters to implement the Kinetic Monte Carlo (KMC) computational upscaling approach. The reason for the higher reactivity of the (100) facet compared to the (010) is explained. [ABSTRACT FROM AUTHOR]

Angiotensin-(1-7) re-balance the Renin-Angiotensin system affected during several pathologies, including the new COVID-19; cardiovascular diseases; and cancer. However, one of the limiting factors for its therapeutic use is its short half-life, which might be overcome with the use of dendrimers as nanoprotectors. In this work, we addressed the following issues: (1) the capacity of our computational protocol to reproduce the experimental structural features of the (hydroxyl/amino)-terminated PAMAM dendrimers as well as the Angiotensin-(1-7) peptide; (2) the coupling of Angiotensin-(1-7) to (hydroxyl/amino)-terminated PAMAM dendrimers in order to gain insight into the structural basis of its molecular binding; (3) the capacity of the dendrimers to protect Angiotensin-(1-7); and (4) the effect of pH changes on the peptide binding and covering. Our Molecular-Dynamics/Metadynamics-based computational protocol well modeled the structural experimental features reported in the literature and our double-docking approach was able to provide reasonable initial structures for stable complexes. At neutral pH, PAMAM dendrimers with both terminal types were able to interact stably with 3 Angiotensin-(1-7) peptides through ASP1, TYR4 and PRO7 key amino acids. In general, they bind on the surface in the case of the hydroxyl-terminated compact dendrimer and in the internal zone in the case of the amino-terminated open dendrimer. At acidic pH, PAMAM dendrimers with both terminal groups are still able to interact with peptides either internalized or in its periphery, however, the number of contacts, the percentage of coverage and the number of hydrogen bonds are lesser than at neutral pH, suggesting a state for peptide release. In summary, amino-terminated PAMAM dendrimer showed slightly better features to bind, load and protect Angiotensin-(1-7) peptides. [ABSTRACT FROM AUTHOR]

The structure, thermodynamic parameters, and the character of thermal motion in octamethylcyclotetrasiloxane (D4) were investigated using the combination of experimental (single-crystal X-ray diffraction, thermochemistry) and theoretical (density functional theory calculations, ab initio molecular dynamics and metadynamics) methods. Single crystals of D4 were grown in a glass capillary in situ and the structures of high- (238–270 K) and low-temperature (100–230 K) phases were studied in detail. In the temperature interval 230–238 K, a phase transition with rather low enthalpy (−1.04(7) kcal/mol) was detected. It was found that phase transition is accompanied by change of conformation of cyclosiloxane moiety from boat-saddle (cradle) to chair. According to PBE0/6-311G(d,p) calculation of isolated D4, such conformation changes are characterized by a low barrier (0.07 kcal/mol). The character of molecular thermal motion and the path of phase transition were established with combination of periodic DFT calculations, including molecular dynamics and metadynamics. The effect of crystal field led to an increase in the calculated phase transition barrier (4.27 kcal/mol from low- to high-temperature phase and 3.20 kcal/mol in opposite direction). [ABSTRACT FROM AUTHOR]

The search for the chemical origins of life represents a long-standing and continuously debated enigma. Despite its exceptional complexity, in the last decades the field has experienced a revival, also owing to the exponential growth of the computing power allowing for efficiently simulating the behavior of matter—including its quantum nature—under disparate conditions found, e.g., on the primordial Earth and on Earth-like planetary systems (i.e., exoplanets). In this minireview, we focus on some advanced computational methods capable of efficiently solving the Schrödinger equation at different levels of approximation (i.e., density functional theory)—such as ab initio molecular dynamics—and which are capable to realistically simulate the behavior of matter under the action of energy sources available in prebiotic contexts. In addition, recently developed metadynamics methods coupled with first-principles simulations are here reviewed and exploited to answer to old enigmas and to propose novel scenarios in the exponentially growing research field embedding the study of the chemical origins of life. [ABSTRACT FROM AUTHOR]

The emergence of pandemic situations originated from severe acute respiratory syndrome (SARS)‐CoV‐2 and its new variants created worldwide medical emergencies. Due to the non‐availability of efficient drugs and vaccines at these emergency hours, repurposing existing drugs can effectively treat patients critically infected by SARS‐CoV‐2. Finding a suitable repurposing drug with inhibitory efficacy to a host‐protein is challenging. A detailed mechanistic understanding of the kinetics, (dis)association pathways, key protein residues facilitating the entry–exit of the drugs with targets are fundamental in selecting these repurposed drugs. Keeping this target as the goal of the paper, the potential repurposing drugs, Nafamostat, Camostat, Silmitasertib, Valproic acid, and Zotatifin with host‐proteins HDAC2, CSK22, eIF4E2 are studied to elucidate energetics, kinetics, and dissociation pathways. From an ensemble of independent simulations, we observed the presence of single or multiple dissociation pathways with varying host‐proteins‐drug systems and quantitatively estimated the probability of unbinding through these specific pathways. We also explored the crucial gateway residues facilitating these dissociation mechanisms. Interestingly, the residues we obtained for HDAC2 and CSK22 are also involved in the catalytic activity. Our results demonstrate how these potential drugs interact with the host machinery and the specific target residues, showing involvement in the mechanism. Most of these drugs are in the preclinical phase, and some are already being used to treat severe COVID‐19 patients. Hence, the mechanistic insight presented in this study is envisaged to support further findings of clinical studies and eventually develop efficient inhibitors to treat SARS‐CoV‐2. [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]

Sugammadex, marketed as Bridion™, is an approved cyclodextrin (CD) based drug for the reversal of neuromuscular blockade in adults undergoing surgery. Sugammadex forms an inclusion complex with the neuromuscular blocking agent (NMBA) rocuronium, allowing rapid reversal of muscle paralysis. In silico methods have been developed for studying CD inclusion complexes, aimed at accurately predicting their structural, energetic, dynamic, and kinetic properties, as well as binding constants. Here, a computational study aimed at characterizing the sugammadex-rocuronium system from the perspective of docking calculations, free molecular dynamics (MD) simulations, and biased metadynamics simulations with potential of mean force (PMF) calculations is presented. The aim is to provide detailed information about this system, as well as to use it as a model system for validation of the methods. This method predicts results in line with experimental evidence for both the optimal structure and the quantitative value for the binding constant. Interestingly, there is a less profound preference for the orientation than might be assumed based on electrostatic interactions, suggesting that both orientations may exist in solution. These results show that this technology can efficiently analyze CD inclusion complexes and could be used to facilitate the development and optimization of novel applications for CDs. [Display omitted] [ABSTRACT FROM AUTHOR]

The carbohydrate binding module 21 (CBM21) from Rhizopus oryzae is a dual-site CBM proposed to disrupt polysaccharide structures. Additionally, it serves as a purification tag in industry. CBM21 crystal structure features a Glc residue in an unusual 1 S 3 conformation, whose relevance for the CBM mechanism of action is unclear. In this context, we seek to contribute for the understanding of CBM21 mechanism of action by: i) investigating the role of the 1 S 3 conformation on carbohydrate recognition, and ii) characterize the protein-carbohydrate binding dynamics using molecular dynamics and metadynamics simulations at MM and QM/MM levels. Results indicate the 1 S 3 Glc conformation is unlikely to occur under biological conditions, being originated from the crystallographic environment. CBM21 binding to small ligands appears transient and unstable, while protein dimerization and polysaccharide chain size influence complex stability. In interactions with amylose, CBM21 exhibits a repeated unbinding followed by re-binding, while simultaneously alternating between binding sites I and II. These results suggest that CBM21 acts through transient interactions, directing carbohydrates to the catalytic center rather than forming strong and long-lasting bonds with carbohydrates. Accordingly, we expect such atomistic depiction of CBM21 mechanism could aid in CBM design targeting biotechnological applications. [Display omitted] [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]

Molecular dynamics (MD) simulation has been widely used in the field of biomedicine to study the conformational transition of proteins caused by mutation or ligand binding/unbinding. It provides some perspectives those are difficult to find in traditional biochemical or pathological experiments, for example, detailed effects of mutations on protein structure and protein–protein/ligand interaction at the atomic level. In this review, a broad overview on conformation changes and drug discovery by MD simulation is given. We first discuss the preparation of protein structure for MD simulation, which is a key step that determines the accuracy of the simulation. Then, we summarize the applications of commonly used force fields and MD simulations in scientific research. Finally, enhanced sampling methods and common applications of these methods are introduced. In brief, MD simulation is a powerful tool and it can be used to guide experimental study. The combination of MD simulation and experimental techniques is an a priori means to solve the biomedical problems and give a deep understanding on the relationship between protein structure and function. [ABSTRACT FROM AUTHOR]

In silico antibody discovery is emerging as a viable alternative to traditional in vivo and in vitro approaches. Many challenges, however, remain open to enabling the properties of designed antibodies to match those produced by the immune system. A major question concerns the structural features of computer-designed complementarity determining regions (CDRs), including the role of conformational entropy in determining the stability and binding affinity of the designed antibodies. To address this problem, we used enhanced-sampling molecular dynamics simulations to compare the free energy landscapes of single-domain antibodies (sdAbs) designed using structure-based (DesAb-HSA-D3) and sequence-based approaches (DesAbO), with that of a nanobody derived from llama immunization (Nb10). Our results indicate that the CDR3 of DesAbO is more conformationally heterogeneous than those of both DesAb-HSA-D3 and Nb10, and the CDR3 of DesAb-HSA-D3 is slightly more dynamic than that of Nb10, which is the original scaffold used for the design of DesAb-HSA-D3. These differences underline the challenges in the rational design of antibodies by revealing the presence of conformational substates likely to have different binding properties and to generate a high entropic cost upon binding. [ABSTRACT FROM AUTHOR]

Glycine (Gly), NH2CH2COOH, is the simplest amino acid. Although it has not been directly detected in the interstellar gas-phase medium, it has been identified in comets and meteorites, and its synthesis in these environments has been simulated in terrestrial laboratory experiments. Likewise, condensation of Gly to form peptides in scenarios resembling those present in a primordial Earth has been demonstrated experimentally. Thus, Gly is a paradigmatic system for biomolecular building blocks to investigate how they can be synthesized in astrophysical environments, transported and delivered by fragments of asteroids (meteorites, once they land on Earth) and comets (interplanetary dust particles that land on Earth) to the primitive Earth, and there react to form biopolymers as a step towards the emergence of life. Quantum chemical investigations addressing these Gly-related events have been performed, providing fundamental atomic-scale information and quantitative energetic data. However, they are spread in the literature and difficult to harmonize in a consistent way due to different computational chemistry methodologies and model systems. This review aims to collect the work done so far to characterize, at a quantum mechanical level, the chemical life of Gly, i.e., from its synthesis in the interstellar medium up to its polymerization on Earth. [ABSTRACT FROM AUTHOR]

[Display omitted] • Training machine learning potentials with active learning and metadynamics. • Ab-initio quality neural network potential for reactive events in solution. • Exploration of metastable and transition states, as well as reaction pathways. • Free energy profiles and kinetic rates of urea decomposition in water. The study of chemical reactions in aqueous media is very important for its implications in several fields of science, from biology to industrial processes. However, modeling these reactions is difficult when water directly participates in the reaction, since it requires a fully quantum mechanical description of the system. Ab-initio molecular dynamics is the ideal candidate to shed light on these processes. However, its scope is limited by a high computational cost. A popular alternative is to perform molecular dynamics simulations powered by machine learning potentials, trained on an extensive set of quantum mechanical calculations. Doing so reliably for reactive processes is difficult because it requires including very many intermediate and transition state configurations. In this study we used an active learning procedure accelerated by enhanced sampling to harvest such structures and to build a neural-network potential to study the urea decomposition process in water. This allowed us to obtain the free energy profiles of this important reaction in a wide range of temperatures, to discover several novel metastable states, and improve the accuracy of the kinetic rates calculations. Furthermore, we found that the formation of the zwitterionic intermediate has the same probability of occurring via an acidic or a basic pathway, which could be the cause of the insensitivity of reaction rates to the solution pH. [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]

Electric fields produce a range of effects by interacting with atoms, molecules, and complex matter modifying the activation barriers of chemical reactions, shaping their free-energy landscapes and reaction pathways, and hence holding a crucial place in catalysis. Owing to the development of novel theories and advanced computational approaches, nowadays supercomputing resources are routinely exploited to investigate the catalytic effects observed when intense electric fields are applied on condensed matter. Within this context, ab initio molecular dynamics simulations coupled with free-energy methods represent unique computational tools allowing for the fine characterization of the role played by static electric fields in activating chemical processes in liquids. Furthermore, the achievement of including crucial nuclear quantum effects in path-integral ab initio molecular dynamics simulations paves the way toward the systematic investigation of the field-induced catalytic effects on matter treated as a fully quantum object. In this review, a series of recent findings on the catalytic effects produced by applying strong electric fields on liquids, with implications not only in technological and industrial realms but also in investigating the "origins of life" enigma, are reported. [ABSTRACT FROM AUTHOR]

In this paper I will present a personal recollection of the development of molecular‐dynamics‐based atomistic simulations in the last forty years. The paper is not meant as a historical account but rather a personal and certainly biased view of the ideas that have underpinned the author's research, allowing ever more complex systems to be studied in an ever more realistic way. [ABSTRACT FROM AUTHOR]

Crystallization of a weakly supercooled Lennard-Jones liquid has been investigated by molecular-dynamics simulation using metadynamics. The Steinhardt order parameter Q6 of a group of particles around a randomly chosen atom and the potential energy of the system are chosen as collective variables for metadynamics simulation of the phase transformation. A change in the values of collective variables above the activation crystallization barrier has been traced. The work of formation of a critical nucleus is estimated. [ABSTRACT FROM AUTHOR]

[Display omitted] • MPXV putative virulence factor is targeted for anti-mpox in silico drug discovery. • Nux-vomica phytochemicals had stable interactions against the virulence protein. • Brincidofovir standard had lowest affinity to MPXV virulence protein. • Nux-vomica phytochemicals had ADMET properties comparable to brincidofovir. • Asn21, Tyr19, Pro17 are key residues in ligand interactions by molecular docking. This study targeted MPXV (mpox virus) virulence factor (MPXV_VF) for anti-mpox drug discovery using Strychnos nux-vomica phytochemicals. Molecular docking showed stronger binding energy of phytochemicals (−7.1–−6.1 kcal/mol) compared to brincidofovir (−5.2–−4.9 kcal/mol). Molecular dynamics simulations authenticated the conformational stability of MPXV_VF-VCN complex. The most potent to inhibit MPXV_VF was VCN that exhibited favourable ADMET profiles comparable to brincidofovir. The metadynamics as a function of distance of Arg85Cα with VCN-C18, and phi Arg85 showed two deepest free energy basins (−129.144 and −109.250 kJ/mol) relative to unbound state. Thus, VCN could be used as main-stream drug candidate for mpox treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • Unique framework with the TiO 6 double defect structure enhances [ZnH]+ generation. • High electron density of [ZnH]+ enhance H-affinity, facilitating C-H activation. • The interaction between Zn and Ti inhibits the loss of Zn. Propane dehydrogenation to propylene has broad application prospects, so it is of great significance to explore low-cost and environmentally friendly catalysts. Metal hydrides, as active sites, exhibit excellent dehydrogenation property. Herein, we report titanium modified [ZnH]+ ([ZnH]+···TiO 6) site with high activity (14.49 mmolC 3 H 6 ·g cat −1·h−1) and regeneration performance, which is derived from the in-situ conversion of [ZnOH]+ in the dehydrogenation reaction. Combined with in-situ spectroscopic characterizations and ab initio molecular dynamics (AIMD) simulations, the unique [ZnH]+···TiO 6 moiety was confirmed, and the evolution process from [ZnOH]+ to [ZnH]+ was clarified. XPS and AIMD calculations show that Zn in the [ZnH]+···TiO 6 structure is in an electron-rich state with high H-affinity, which can effectively reduce the propyl C-H cleavage barriers based on slow-growth simulations. In general, titanium modification can effectively stabilize the [ZnH]+ species and enrich the electrons density of zinc, which contribute to the enhanced PDH performance. [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]

In the field of magnesium-containing silicate glass alteration under aqueous conditions, enstatite glass (MgSiO 3) is used as a valuable system to investigate reaction pathways occurring in its hydrated form by means of Ab-Initio methods. In contrast to previous dissolution studies in which the water molecules interacted only at the glass surface or with small molecular clusters, here we follow reaction pathways for water molecules introduced in the voids of a realistic glass structure. Metadynamics combined with atomic charges derived from electrostatic potential suggest that water dissociation follows a two-step scheme: at first, the water molecule interacts with a SiO 4 or MgO x (x ≥ 3) structural unit via dipole–dipole or dipole–charge interactions, and second, a proton transfer occurs. It also appears that SiOH-Mg hydrolysis reactions are the more likely to occur. Furthermore, it is inferred that pathways exist for complete H 2 O dissociation in two H + and one O 2 − ions, leading to new bonding between the free oxygen ion and Si or Mg cations forming the network. This phenomenon could probably counterbalance hydrolysis and depolymerization by increasing again network connectivity. Several bond dissociation energies are evaluated and the Mg O bond dissociation enthalpy from the Mg OHSi linkage is derived to be 1.34 eV (or 128.84 kJ mol−1). [Display omitted] [ABSTRACT FROM AUTHOR]

Molecular functionality can be often directly attributed to given properties of the electronic wavefunction. Analogous to the potential energy surface, these properties can be represented as a function of the nuclear coordinates, giving rise to molecular "functional landscapes." However, so far there has been no possibility for their systematic investigation. This perspective aims to discuss the development of new theoretical methods based on the multistate extension of the metadynamics approach, employing electronic collective variables. This emerging methodology allows to explore functional landscapes and to gain a deeper understanding of the structure–function relation in molecules and complex molecular systems in the ground and excited electronic state. [ABSTRACT FROM AUTHOR]

Methods that combine collective variable (CV) based enhanced sampling and global tempering approaches are used in speeding‐up the conformational sampling and free energy calculation of large and soft systems with a plethora of energy minima. In this paper, a new method of this kind is proposed in which the well‐sliced metadynamics approach (WSMTD) is united with replica exchange with solute tempering (REST2) method. WSMTD employs a divide‐and‐conquer strategy wherein high‐dimensional slices of a free energy surface are independently sampled and combined. The method enables one to accomplish a controlled exploration of the CV‐space with a restraining bias as in umbrella sampling, and enhance‐sampling of one or more orthogonal CVs using a metadynamics like bias. The new hybrid method proposed here enables boosting the sampling of more slow degrees of freedom in WSMTD simulations, without the need to specify associated CVs, through a replica exchange scheme within the framework of REST2. The high‐dimensional slices of the probability distributions of CVs computed from the united WSMTD and REST2 simulations are subsequently combined using the weighted histogram analysis method to obtain the free energy surface. We show that the new method proposed here is accurate, improves the conformational sampling, and achieves quick convergence in free energy estimates. We demonstrate this by computing the conformational free energy landscapes of solvated alanine tripeptide and Trp‐cage mini protein in explicit water. [ABSTRACT FROM AUTHOR]

Temperature accelerated sliced sampling (TASS) is an efficient method to compute high dimensional free energy landscapes. The original TASS method employs the weighted histogram analysis method (WHAM) which is an iterative post‐processing to reweight and stitch high dimensional probability distributions in sliced windows that are obtained in the presence of restraining biases. The WHAM necessitates that TASS windows lie close to each other for proper overlap of distributions and span the collective variable space of interest. On the other hand, increase in number of TASS windows implies more number of simulations, and thus it affects the efficiency of the method. To overcome this problem, we propose herein a new mean‐force (MF) based reweighting scheme called TASS‐MF, which enables accurate computation with a fewer number of windows devoid of the WHAM post‐processing. Application of the technique is demonstrated for alanine di‐ and tripeptides in vacuo to compute their two‐ and four‐dimensional free energy landscapes, the latter of which is formidable in conventional umbrella sampling and metadynamics. The landscapes are computed within a kcal mol−1 accuracy, ensuring a safe usage for broad applications in computational chemistry. [ABSTRACT FROM AUTHOR]

Extensive classical and quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations are used to establish the structural features of the O state in bacteriorhodopsin (bR) and its conversion back to the bR ground state. The computed free energy surface is consistent with available experimental data for the kinetics and thermodynamics of the O to bR transition. The simulation results highlight the importance of the proton release group (PRG, consisting of Glu194/204) and the conserved arginine 82 in modulating the hydration level of the protein cavity. In particular, in the O state, deprotonation of the PRG and downward rotation of Arg82 lead to elevated hydration level and a continuous water network that connects the PRG to the protonated Asp85. Proton exchange through this water network is shown by ~0.1-#956;s semiempirical QM/MM free energy simulations to occur through the generation and propagation of a proton hole, which is relayed by Asp212 and stabilized by Arg82. This mechanism provides an explanation for the observation that the D85S mutant of bacteriorhodopsin pumps chloride ions. The electrostatics-hydration coupling mechanism and the involvement of all titration states of water are likely applicable to many biomolecules involved in bioenergetic transduction. [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]