Metadynamics Simulations Research Articles

Ammonolysis of Glyoxal at the Air‐Water Nanodroplet Interface

AbstractThe reactions of glyoxal (CHO)2) with amines in cloud processes contribute to the formation of brown carbon and oligomer particles in the atmosphere. However, their molecular mechanisms remain unknown. Herein, we investigate the ammonolysis mechanisms of glyoxal with amines at the air‐water nanodroplet interface. We identified three and two distinct pathways for the ammonolysis of glyoxal with dimethylamine and methylamine by using metadynamics simulations at the air‐water nanodroplet interface, respectively. Notably, the stepwise pathways mediated by the water dimer for the reactions of glyoxal with dimethylamine and methylamine display the lowest free energy barriers of 3.6 and 4.9 kcal ⋅ mol−1, respectively. These results showed that the air‐water nanodroplet ammonolysis reactions of glyoxal with dimethylamine and methylamine were more feasible and occurred at faster rates than the corresponding gas phase ammonolysis, the OH+(CHO)2 reaction, and the aqueous phase reaction of glyoxal, leading to the dominant removal of glyoxal. Our results provide new and important insight into the reactions between carbonyl compounds and amines, which are crucial in forming nitrogen‐containing aerosol particles.

Ammonolysis of Glyoxal at the Air-Water Nanodroplet Interface.

The reactions of glyoxal (CHO)2 ) with amines in cloud processes contribute to the formation of brown carbon and oligomer particles in the atmosphere. However, their molecular mechanisms remain unknown. Herein, we investigate the ammonolysis mechanisms of glyoxal with amines at the air-water nanodroplet interface. We identified three and two distinct pathways for the ammonolysis of glyoxal with dimethylamine and methylamine by using metadynamics simulations at the air-water nanodroplet interface, respectively. Notably, the stepwise pathways mediated by the water dimer for the reactions of glyoxal with dimethylamine and methylamine display the lowest free energy barriers of 3.6 and 4.9 kcal ⋅ mol-1 , respectively. These results showed that the air-water nanodroplet ammonolysis reactions of glyoxal with dimethylamine and methylamine were more feasible and occurred at faster rates than the corresponding gas phase ammonolysis, the OH+(CHO)2 reaction, and the aqueous phase reaction of glyoxal, leading to the dominant removal of glyoxal. Our results provide new and important insight into the reactions between carbonyl compounds and amines, which are crucial in forming nitrogen-containing aerosol particles.

Structures of Th4+ aqueous solutions: insights from AIMD and metadynamics simulations.

Solution chemistry of actinide ions is critical to understanding the solvation behaviors and hydrolysis process. Using tetravalent thorium ion Th4+ as a representative example, we investigate the local structures and dynamic behaviors of hydrated Th4+ ions by ab initio molecular dynamics (AIMD) simulations using the recently developed norm-conserving pseudopotentials and basis sets optimized for actinides (J.-B. Lu et al., J. Chem. Theory Comput. 2021, 17, 3360-3371). AIMD simulations reveal two distinct solvation shells, with the first shell comprising 9 water molecules at approximately rTh-O = 2.50 Å and exhibiting a tricapped trigonal prism geometry. These conclusions are confirmed through metadynamics simulations and further structural analysis. AIMD simulations also show the slight effect of temperature and counterions on the structure of the solution. The structured solvation shells of the highly charged Th4+ ion with the specific geometry, distinct from the structure of liquid water, lead to corresponding structural changes in the hydrogen bond network in water. Additionally, beyond the solvent-shared ion pair (SIP) state observed in the unbiased AIMD simulations, the metadynamics simulations reconstruct a two-dimensional free energy surface that clearly indicates the potential stability of the contact ion pair (CIP) state in the system with Cl- as a counterion. The findings in this work provide insights into the solution chemistry of actinides and serve as a reference for studying other actinide solution systems.

Synthesis, biological evaluation and metadynamics simulations of novel N-methyl β-sheet breaker peptides as inhibitors of Alzheimer's β-amyloid fibrillogenesis

We report the synthesis and in vitro evaluation of novel beta-sheet breaker peptides as promising Aβ fibrillogenesis inhibitors. Further 3D-GRID pharmacophore and metadynamics simulations rationalized the design of these peptides.

Computational analysis of R-X oxidative addition to Pd nanoparticles.

Oxidative addition (OA) is a necessary step in mechanisms of widely used synthetic methodologies such as the Heck reaction, cross-coupling reactions, and the Buchwald-Hartwig amination. This study pioneers the exploration of OA of aryl halide to palladium nanoparticles (NPs), a process previously unaddressed in contrast to the activity of well-studied Pd(0) complexes. Employing DFT modeling and semi-empirical metadynamics simulations, the oxidative addition of phenyl bromide to Pd nanoparticles was investigated in detail. Energy profiles of oxidative addition to Pd NPs were analyzed and compared to those involving Pd(0) complexes forming under both ligand-stabilized (phosphines) and ligandless (amine base) conditions. Metadynamics simulations highlighted the edges of the (1 1 1) facets of Pd NPs as the key element of oxidative addition activity. We demonstrate that OA to Pd NPs is not only kinetically facile at ambient temperatures but also thermodynamically favorable. This finding accentuates the necessity of incorporating OA to Pd NPs in future investigations, thus providing a more realistic view of the involved catalytic mechanisms. These results enhance the understanding of aryl halide (cross-)coupling reactions, reinforcing the concept of a catalytic "cocktail". This concept posits dynamic interconversions between diverse active and inactive centers, collectively affecting the outcome of the reaction. High activity of Pd NPs in direct C-X activation paves the way for novel approaches in catalysis, potentially enhancing the field and offering new catalytic pathways to consider.

Structural and thermodynamic characterization of allosteric transitions in human serum albumin with metadynamics simulations.

Human serum albumin (HSA) is the most prominent protein in blood plasma, responsible for the maintenance of blood viscosity and transport of endogenous and exogenous molecules. Fatty acids (FA) are the most common ligands of HSA and their binding can modify the protein's structure. The protein can assume two well-defined conformations, referred to as 'Neutral' and 'Basic'. The Neutral (N) state occurs at pH close to 7.0 and in the absence of bound FA. The Basic (B) state occurs at pH higher than 8.0 or when the protein is bound to long-chain FA. HSA's allosteric behaviour is dependent on the number on FA bound to the structure. However, the mechanism of this allosteric regulation is not clear. To understand how albumin changes its conformation, we compared a series of HSA structures deposited in the protein data bank to identify the minimum amount of FA bound to albumin, which is enough to drive the allosteric transition. Thereafter, non-biased molecular dynamics (MD) simulations were used to track protein's dynamics. Surprisingly, running an ensemble of relatively short MD simulations, we observed rapid transition from the B to the N state. These simulations revealed differences in the mobilities of the protein's subdomains, with one domain unable to fully complete its transition. To track the transition dynamics in full, we used these results to choose good geometrical collective variables for running metadynamics simulations. The metadynamics calculations showed that there was a low energy barrier for the transition from the B to the N state, while a higher energy barrier was observed for the N to the B transition. These calculations also offered valuable insights into the transition process.

Phase-dependent polymerization isomerism in the coordination complexes of a flexible bis(β-diketonato) ligand.

First prepared in the late 70s, the pro-ligand 1,3-bis(3,5-dioxo-1-hexyl)benzene (H2bdhb) contains two acetoacetyl terminations linked to a central 1,3-phenylene unit through dimethylene bridges. Since each termination can be either in diketonic or keto-enolic form, in organic solution it exists as a mixture of three spectroscopically resolvable tautomers. In the presence of pyridine, Co2+ and the bdhb2- anion form a crystalline dimeric compound with formula [Co2(bdhb)2(py)4] (2) and a Co⋯Co separation of more than 11 Å. Complex 2 contains two pseudo-octahedrally coordinated and non-interacting high-spin cobalt(II) ions (S = 3/2) displaying a large easy-plane anisotropy (D ∼ 70 cm-1), as consistently indicated by magnetic measurements, X-band EPR spectra, and complete active space self-consistent field/N-electron valence state perturbation theory (CASSCF/NEVPT2) calculations. At cryogenic temperatures (T < 7 K) and in an applied static magnetic field, the compound shows detectably slow magnetic relaxation, which occurs through direct and Raman mechanisms. Combined mass spectrometry, UV-Vis, and 1H/2H NMR data, including an isotopic labelling experiment and a determination of molecular weight by diffusion ordered spectroscopy (DOSY), show that 2 rearranges to monomeric high-spin [Co(bdhb)(py)x] species (x = 0, 1, or 2) in organic solution (CH2Cl2, THF) with concomitant partial dissociation of the py ligands. The X-band EPR spectra in a frozen CH2Cl2/toluene matrix concurrently suggest a significant alteration of the coordination environment upon dissolution. These observations are fairly well reproduced by density functional theory (DFT) and CASSCF/NEVPT2 calculations on the lowest Gibbs free energy conformers of each species, as provided by an extensive conformational search based on meta-dynamics simulations and semiempirical tight-binding methods. After the vanadyl analogue, compound 2 provides the second example of polymerization isomerism in the 1 : 1 adducts of bdhb2- with divalent metal ions.

Orbital and free energy landscape expedition towards the unexplored catalytic realm of aromatically modified FLPs for CO2 sequestration.

The emergence of frustrated Lewis pairs (FLPs) has created a whole new dimension in the development of metal free catalysts for CO2 sequestration. Efforts have been made to enhance the catalytic activity of the FLPs. The aromatic modulation of the catalytic sites has been successfully demonstrated to enhance the activity towards CO2. Although various aromatically modified geminal FLPs have been investigated for CO2 capture, the catalytic space of these FLPs has not been fully resolved yet. Thus, to fulfil the knowledge gap in the understanding of the catalytic behaviour and to extend the concept of aromatically enhanced FLPs, in the present study all the possible combinations of aromatic and antiaromatic modulations of the acidic and basic sites have been proposed and examined using density functional theory based orbital analysis. Further to verify the results obtained from the orbital analysis and to fully explore the catalytic space of the proposed systems, free energy landscapes have been examined using metadynamics simulations. The detailed intrinsic bond orbital (IBO) and principal interacting orbital (PIO) analyses capture crucial details of the reactions. Furthermore, evolution of anisotropy of induced current density (AICD) along the reaction justifies the effect of aromatic/antiaromatic modulation on the catalytic sites. The results show that highly asynchronous mechanisms have been found due to the aromatic/antiaromatic modulations. The simultaneous favourable aromatic/antiaromatic modification on the acidic and basic sites may greatly reduce the CO2 activation barrier. The enhancement of the acidic character of the B atom in the intramolecular FLPs (IFLPs) leads to a thermodynamically more feasible reaction with stable CO2 adducts. The acidic site has been found to play a major role in controlling the kinetics and thermodynamics of the reaction. This study provides valuable insights into the catalytic realm of the aromatically modified FLPs, which can be utilized to design more efficient and specific next-generation FLPs.

Can local heating and molecular crowders disintegrate amyloid aggregates?

The present study employs a blend of molecular dynamics simulations and a theoretical model to explore the potential disintegration mechanism of a matured Aβ octamer, aiming to offer a strategy to combat Alzheimer's disease. We investigate local heating and crowding effects on Aβ disintegration by selectively heating key Aβ segments and varying the concentration of sodium dodecyl sulphate (SDS), respectively. Despite initiation of disruption, Aβ aggregates resist complete disintegration during local heating due to rapid thermal energy distribution to the surrounding water. Conversely, although SDS molecules effectively inhibit Aβ aggregation at higher concentration through micelle formation, they fail to completely disintegrate the aggregate due to the exceedingly high energy barrier. To address the sampling challenge posed by the formidable energy barrier, we have performed well-tempered metadynamics simulations. Simulations reveal a multi-step disintegration mechanism for the Aβ octamer, suggesting a probable sequence: octamer → pentamer/hexamer ⇌ tetramer → monomer, with a rate-determining step constituting 45 kJ mol-1 barrier during the octamer to pentamer/hexamer transition. Additionally, we have proposed a novel two-state mean-field model based on Ising spins that offers an insight into the kinetics of the Aβ growth process and external perturbation effects on disintegration. Thus, the current simulation study, coupled with the newly introduced mean-field model, offers an insight into the detailed mechanisms underlying the Aβ aggregation process, guiding potential strategies for effective disintegration of Aβ aggregates.

Assessing the role of residue Phe108 of cytochrome P450 3A4 in allosteric effects of midazolam metabolism.

Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more drugs in clinical use than any other xenobiotic-metabolizing enzyme. CYP3A4-mediated drug metabolism is usually allosterically modulated by substrate concentration (homotropic allostery) and other drugs (heterotropic allostery), exhibiting unusual kinetic profiles and regiospecific metabolism. Recent studies suggest that residue Phe108 (F108) of CYP3A4 may have an important role in drug metabolism. In this work, residue mutations were coupled with well-tempered metadynamics simulations to assess the importance of F108 in the allosteric effects of midazolam metabolism. Comparing the simulation results of the wild-type and mutation systems, we identify that the π-π interaction and steric effect between the F108 side chain and midazolam is favorable for the stable binding of substrate in the active site. F108 also plays an important role in the transition of substrate binding mode, which mainly induces the transition of substrate binding mode by forming π-π interactions with multiple aromatic rings of the substrate. Moreover, the side chain of F108 is closely related to the radius and depth of the 2a and 2f channels, and F108 may further regulate drug metabolism by affecting the pathway, orientation, or time of substrate entry into the CYP3A4 active site or product egress from the active site. Altogether, we suggest that F108 affects drug metabolism and regulatory mechanisms by affecting substrate binding stability, binding mode transition, and channel characteristics of CYP3A4. Our findings could promote the understanding of complicated allosteric mechanisms in CYP3A4-mediated drug metabolism, and the knowledge could be used for drug development and disease treatment.

Metadynamics simulations reveal alloying-dealloying processes for bimetallic PdGa nanoparticles under CO2 hydrogenation.

Supported bimetallic nanoparticles (NPs) often display improved catalytic performances (activity and/or selectivity). Yet, structure-activity relationships are difficult to derive due to the multitude of possible compositions, interfaces and alloys. This is notably true for bimetallic NPs used in the selective hydrogenation of CO2 to methanol, where the NPs respond dynamically to the chemical potential of the reactants and products. Herein, we use a combined computational and experimental approach that leverages ab initio Molecular Dynamics (AIMD) and Metadynamics (MTD) in conjunction with in situ X-ray absorption spectroscopy, chemisorption and CO-IR, to explore the dynamic structures and interactions with adsorbates under various CO2 hydrogenation conditions in highly active and selective silica-supported PdGa NPs. We find that PdGa alloying generates isolated Pd sites at the NP surface, changing the dominant binding modes of relevant adsorbates compared to pure Pd NPs: CO molecules mainly occupy atop sites and hydrides switch from mainly internal to atop and bridge sites. Under more oxidizing conditions, akin to CO2 hydrogenation, Ga is partially oxidized, forming a GaOX layer on the NP surface, with a partially dealloyed PdGa core and some remaining isolated Pd surface sites. Overall, these bimetallic NPs show high structural dynamics and a variable extent of alloying depending on the adsorbates relevant to CO2 hydrogenation. This work highlights that AIMD/MTD is a powerful approach to elucidate structural dynamics at a single particle level in complex catalytic systems.

Dynamic dissolution of Cm3+ ions incorporated at the calcite-water interface: an ab initio molecular dynamics simulation study.

The stability of actinide-mineral solid solution in a water environment is critical for assessing the safety of nuclear-waste geological repositories and studying actinide migration in natural systems. However, the dissolution behavior of actinide ions incorporated at the mineral-water interface is still unclear at the atomic level. Herein, we present metadynamics simulations of the reaction pathways, thermodynamics and kinetics of trivalent curium ions (Cm3+) dissolving from calcite surfaces. Cm3+ ions incorporated in different calcite surfaces (i.e., terrace and stepped surfaces) with distinct coordination environments have different reaction pathways, free energy barriers and free energy changes. We found that Cm dissolution from a stepped surface is more favorable than that from a terrace surface, both thermodynamically and kinetically. In addition, water molecules seem to promote the detachment of curium ions from the surface by exerting a pulling force via water coordination with Cm3+ and a pushing force via proton migration to the surface layer and water diffusion in the vacant Cm site. Thus, the findings from this work prove to be a milestone in revealing the dynamic dissolution mechanism of trivalent actinides from minerals and would also help predict the dissolution behaviors of other metal ions at the solid-water interface in chemical and environmental sciences.

Phase diagram of ZIF-4 from computer simulations

Well-tempered metadynamics simulations are employed to explore the phase diagram of ZIF-4, a porous crystalline metal–organic framework of industrial relevance.

Stable and accurate atomistic simulations of flexible molecules using conformationally generalisable machine learned potentials.

Computational simulation methods based on machine learned potentials (MLPs) promise to revolutionise shape prediction of flexible molecules in solution, but their widespread adoption has been limited by the way in which training data is generated. Here, we present an approach which allows the key conformational degrees of freedom to be properly represented in reference molecular datasets. MLPs trained on these datasets using a global descriptor scheme are generalisable in conformational space, providing quantum chemical accuracy for all conformers. These MLPs are capable of propagating long, stable molecular dynamics trajectories, an attribute that has remained a challenge. We deploy the MLPs in obtaining converged conformational free energy surfaces for flexible molecules via well-tempered metadynamics simulations; this approach provides a hitherto inaccessible route to accurately computing the structural, dynamical and thermodynamical properties of a wide variety of flexible molecular systems. It is further demonstrated that MLPs must be trained on reference datasets with complete coverage of conformational space, including in barrier regions, to achieve stable molecular dynamics trajectories.

Interfacial rheology of lanthanide binding peptide surfactants at the air-water interface.

Peptide surfactants (PEPS) are studied to capture and retain rare earth elements (REEs) at air-water interfaces to enable REE separations. Peptide sequences, designed to selectively bind REEs, depend crucially on the position of ligands within their binding loop domain. These ligands form a coordination sphere that wraps and retains the cation. We study variants of lanthanide binding tags (LBTs) designed to complex strongly with Tb3+. The peptide LBT5- (with net charge -5) is known to bind Tb3+ and adsorb with more REE cations than peptide molecules, suggesting that undesired non-specific coulombic interactions occur. Rheological characterization of interfaces of LBT5- and Tb3+ solutions reveal the formation of an interfacial gel. To probe whether this gelation reflects chelation among intact adsorbed LBT5-:Tb3+ complexes or destruction of the binding loop, we study a variant, LBT3-, designed to form net neutral LBT3-:Tb3+ complexes. Solutions of LBT3- and Tb3+ form purely viscous layers in the presence of excess Tb3+, indicating that each peptide binds a single REE in an intact coordination sphere. We introduce the variant RR-LBT3- with net charge -3 and anionic ligands outside of the coordination sphere. We find that such exposed ligands promote interfacial gelation. Thus, a nuanced requirement for interfacial selectivity of PEPS is proposed: that anionic ligands outside of the coordination sphere must be avoided to prevent the non-selective recruitment of REE cations. This view is supported by simulation, including interfacial molecular dynamics simulations, and interfacial metadynamics simulations of the free energy landscape of the binding loop conformational space.

Synthesis of C-glycoside analogues of isopropyl β-D-1-thiogalactopyranoside (IPTG) and 1-β-D-galactopyranosyl-2-methylpropane. Conformational analysis and evaluation as inhibitors of the lac repressor in E. coli and as galactosidase inhibitors.

Isopropyl 1-thio-β-D-galactopyranoside (IPTG, 1) is used widely as an inducer of protein expression in E. coli and 1-β-D-galactopyranosyl-2-methylpropane (2), a C-glycoside analogue of 1, has also been identified as an inducer. Here, synthesis and study of mimetics of 1 and 2, 1-β-D-galactopyranosyl-2-methylpropan-1-ols and two cyclic acetals derivatives, that constrain the presentation of the iPr group in various geometries is described. Conformational analysis of C-glycosides in protic solvent is performed using (i) Desmond metadynamics simulations (OPLS4) and (ii) use of 3JHH values obtained by 1H-NMR spectroscopy. 1-β-D-Galactopyranosyl-2-methylpropane (2) is an effective protein expression inducer when compared to the new mimetics, which were less effective or did not induce expression. 1-β-D-Galactopyranosyl-2-methylpropane (2) led to significantly reduced proteolysis during protein expression, compared to IPTG suggesting that recombinant protein purification will be easier to achieve with 2, yielding proteins with higher quality and activity. IPTG reduced bacterial growth to a greater degree than 2 compared to the control. IPTG's isopropyl group was observed by molecular dynamics (MD) simulations to be flexible in the binding pocket, deviating from its crystal structure binding mode, without impacting other interactions. The MD simulations predicted that 1-β-D-galactopyranosyl-2-methylpropane (2) was more likely than IPTG to bind the repressor with a conformation favoured in protic solvent, while maintaining interactions observed for IPTG. MD simulations predicted that isobutanol derivatives may disrupt interactions associated with IPTG's binding mode. The compounds were also evaluated as inhibitors of galactosidases, with 2 being the more potent inhibitor of the E. coli β-galactosidase. The constrained cyclic acetals showed similar inhibition constants to IPTG indicating E. coli β-galactosidase can recognize galactopyranoses with varying presentation of the iPr group.

Temperature-dependent Li-ion transport in lithium lanthanum titanate electrolytes.

A shift of the Li+ ion hopping mechanism with temperature in solid-state lithium lanthanum titanate (LLTO) electrolytes was discovered using ab initio metadynamics simulations. The low-temperature potential-energy barriers were calculated for pristine, nitrogen-doped, vacancy-containing LLTO, revealing nitrogen dopants in the La-poor layer and oxygen vacancies as the key factors for enhanced ionic conductivity.

Uncovering New Conformational States of the Substrate Binding Pocket of LSD1 Potential for Inhibitor Design via Funnel Metadynamics.

Lysine-specific demethylase 1 (LSD1) is a promising therapeutic target for cancer therapy. So far, over 80 crystal structures of LSD1 in different complex states have been deposited in the Protein Data Bank, which are valuable resources for performing structure-based drug design. However, among all of the crystal structures of LSD1, the substrate binding pocket, which is the most efficient druggable site for designing LSD1 inhibitors at present, is very similar no matter whether LSD1 is in the apo or any holo forms, which is inconsistent with its versatile demethylase functions. To investigate whether the substrate binding pocket is rigid or exhibits other representative conformations different from the crystal conformations that are feasible for designing new LSD1 inhibitors, we performed funnel metadynamics simulations to study the conformation dynamics of LSD1 in the binding process of two effective LSD1 inhibitors (CC-90011 and 6X0, CC-90011 undergoing clinical trials). Our results showed that the entrance of the substrate binding pocket is very flexible. Two representative entrance conformations of LSD1 counting against binding with the substrate of histone H3 were detected, which may be used for structure-based LSD1 inhibitor design. Besides, alternative optimal binding modes and prebinding modes for both inhibitors were also detected, which depicted that the key interactions changed along with the binding process. Our results should provide great help for LSD1 inhibitor design.

Attempting Well-Tempered Funnel Metadynamics Simulations for the Evaluation of the Binding Kinetics of Methionine Aminopeptidase-II Inhibitors.

Understanding the unbinding kinetics of protein-ligand complexes is considered a significant approach for the design of ligands with desired specificity and safety. In recent years, enhanced sampling methods have emerged as effective tools for studying the unbinding kinetics of protein-ligand complexes at the atomistic level. MetAP-II is a target for the treatment of cancer for which not a single effective drug is available yet. The identification of the dissociation rate of ligands from the complexes often serves as a better predictor for in vivo efficacy than the ligands' binding affinity. Here, funnel-based restraint well-tempered metadynamics simulations were applied to predict the residence time of two ligands bound to MetAP-II, along with the ligand association and dissociation mechanism involving the identification of the binding hotspot during ligand egress. The ligand-egressing route revealed by metadynamics simulations also correlated with the identified pathways from the CAVER analysis and by the enhanced sampling simulation using PLUMED. Ligand 1 formed a strong H-bond interaction with GLU364 estimating a higher residence time of 28.22 ± 5.29 ns in contrast to ligand 2 with a residence time of 19.05 ± 3.58 ns, which easily dissociated from the binding pocket of MetAP-II. The results obtained from the simulations were consistent to reveal ligand 1 being superior to ligand 2; however, the experimental data related to residence time were close for both ligands, and no kinetic data were available for ligand 2. The current study could be considered the first attempt to apply an enhanced sampling method for the evaluation of the binding kinetics and thermodynamics of two different classes of ligands to a binuclear metalloprotein.

Hydrogen Transport Between Layers of Transition Metal‐Dichalcogenides

AbstractHydrogen is a crucial source of green energy and is extensively studied for its potential usage in fuel cells. The advent of 2D crystals (2DCs) has taken hydrogen research to new heights, enabling it to tunnel through layers of 2DCs or be transported within voids between the layers, as demonstrated in recent experiments by Geim's group. In this study, it investigates how the composition and stacking of transition‐metal dichalcogenide (TMDC) layers influence the transport and self‐diffusion coefficients (D) of hydrogen atoms using well‐tempered metadynamics (WTMetaD) simulations. The findings show that modifying either the transition metal or the chalcogen atoms significantly affects the free energy barriers (ΔF) and, consequently, the self‐diffusion of hydrogen atoms between the 2DC layers. In the polytype (2H stacking), MoSe2 exhibits the lowest ΔF, while WS2 has the highest, resulting in the largest D for the former system. Additionally, hydrogen atoms inside the (or 3R) polytype encounter more than twice lower energy barriers and, thus, much higher diffusivity compared to those within the most stable stacking. These findings are particularly significant when investigating twisted layers or homo‐ or heterostructures, as different stacking areas may dominate over others, potentially leading to directional transport and interesting materials for ion or atom sieving.