Classical MD Research Articles

Importance of Nuclear Quantum Effects on Aqueous Electrolyte Transport under Confinement in Ti3C2 MXenes.

Protons display a high chemical activity and strongly affect the charge storage capability in confined interlayer spaces of two-dimensional (2D) materials. As such, an accurate representation of proton dynamics under confinement is important for understanding and predicting charge storage dynamics in these materials. While often ignored in atomistic-scale simulations, nuclear quantum effects (NQEs), e.g., tunneling, can be significant under confinement even at room temperature. Using the thermostatted ring polymer molecular dynamics implementation of path integral molecular dynamics (PIMD) in conjunction with the ReaxFF force field, density functional tight binding (DFTB), and NequIP neural network potential simulations, we investigate the role of NQEs on proton and water transport in bulk water and aqueous electrolytes under confinement in Ti3C2 MXenes. Although overall NQEs are relatively small, especially in bulk, we find that they can alter both quantitative values and qualitative trends on both proton transport and water self-diffusion under confinement relative to classical MD predictions. Therefore, our results suggest the need for NQEs to be considered to simulate aqueous systems under confinement for both qualitative and quantitative accuracy.

Influence of DPPE surface undulations on melting temperature determination: UV/Vis spectroscopic and MD study

One of the most distinguished quantities that describes lipid main phase transition, i.e. the transition from the gel (Lβ(′)) to the fluid (Lα) phase, is its melting temperature (Tm). Because melting is accompanied by a large change in enthalpy the, Lβ(′) → Lα transition can be monitored by various calorimetric, structural and spectroscopic techniques and Tm should be the same regardless of the metric monitored or the technique employed. However, in the case of DPPE multilamellar aggregates there is a small but systematic deviation of Tm values determined by DSC and FTIR spectroscopy. The aim of this paper is to explain this discrepancy by combined UV/Vis spectroscopic and MD computational approach. Multivariate analysis performed on temperature-dependent UV/Vis spectra of DPPE suspensions demonstrated that at 55 ± 1 °C certain phenomenon causes a small but detectable change in suspension turbidity, whereas a dominant change in the latter is registered at 63.2 ± 0.4 °C that coincides with Tm value determined from DSC curve. If this effect should be ignored, the overall data give Tm value the same as FTIR spectra data (61.0 ± 0.4 °C). As the classical MD simulations suggest that about 10° below Tm certain undulations appear at the surface of DPPE bilayers, we concluded that certain discontinuities in curvature fluctuations arise at reported temperature which are to some extent coupled with lipid melting. Ultimately, such events and the associated changes in curvature affect Tm value measured by different techniques.

Unravelling interactions between active site residues and DMAP in the initial steps of prenylated flavin mononucleotide biosynthesis catalyzed by PaUbiX

BackgroundPrenylated flavin mononucleotide (prFMN) is a recently discovered, heavily modified flavin compound. It is the only known cofactor that enables enzymatic 1,3-dipolar cycloaddition reactions. It is produced by enzymes from the UbiX family, from flavin mononucleotide and either dimethylallyl mono- or diphosphate. prFMN biosynthesis is currently reported to be initiated by protonation of the substrate by Glu140. MethodsComputational chemistry methods are applied herein - Constant pH MD, classical MD simulations, and QM cluster optimizations. ResultsGlu140 competes for a single proton with Lys129 prior to prFMN biosynthesis, but it is the latter that adopted a protonated state. Once the prenyl-FMN adduct is formed, Glu140 occurs in a protonated state far more often, while the occupancy of protonated Lys129 does not change. Lys129, Glu140, and Arg122 seem to play a key role in either stabilizing or protonating DMAP phosphate group within the PaUbiX active site throughout initial steps of prFMN biosynthesis. ConclusionsThe role of Lys129 in the functioning of PaUbiX is reported for the first time. Glu140 is unlikely to act as a proton donor in prFMN biosynthesis. Instead, Lys129 and Arg122 fulfil this role. Glu140 still plays a role in contributing to hydrogen-bond network. This behavior is most likely conserved throughout the UbiX family due to the structural similarity of the active sites of those proteins. SignificanceMechanistic insights into a crucial biochemical process, the biosynthesis of prFMN, are provided. This study, although purely computational, extends and perfectly complements the knowledge obtained in classical laboratory experiments.

Structural Reshaping of the Zinc-Finger Domain of the SARS-CoV-2 nsp13 Protein Using Bismuth(III) Ions: A Multilevel Computational Study.

The identification of novel therapeutics against the pandemic SARS-CoV-2 infection is an indispensable new address of current scientific research. In the search for anti-SARS-CoV-2 agents as alternatives to the vaccine or immune therapeutics whose efficacy naturally degrades with the occurrence of new variants, the salts of Bi3+ have been found to decrease the activity of the Zn2+-dependent non-structural protein 13 (nsp13) helicase, a key component of the SARS-CoV-2 molecular tool kit. Here, we present a multilevel computational investigation based on the articulation of DFT calculations, classical MD simulations, and MIF analyses, focused on the examination of the effects of Bi3+/Zn2+ exchange on the structure and molecular interaction features of the nsp13 protein. Our calculations confirmed that Bi3+ ions can replace Zn2+ in the zinc-finger metal centers and cause slight but appreciable structural modifications in the zinc-binding domain of nsp13. Nevertheless, by employing an in-house-developed ATOMIF tool, we evidenced that such a Bi3+/Zn2+ exchange may decrease the extension of a specific hydrophobic portion of nsp13, responsible for the interaction with the nsp12 protein. The present study provides for a detailed, atomistic insight into the potential anti-SARS-CoV-2 activity of Bi3+ and, more generally, evidences the hampering of the nsp13–nsp12 interaction as a plausible therapeutic strategy.

Chemical effects on the dynamics of organic molecules irradiated with high intensity x rays.

The interaction of a high intensity x-ray pulse with matter causes ionization of the constituent atoms through various atomic processes, and the system eventually goes through a complex structural dynamics. Understanding this whole process is important from the perspective of structure determination of molecules using single particle imaging. XMDYN, which is a classical molecular dynamics-Monte Carlo based hybrid approach, has been successful in simulating the dynamical evolution of various systems under intense irradiation over the past years. The present study aims for extending the XMDYN toolkit to treat chemical bonds using the reactive force field. In order to study its impact, a highly intense x-ray pulse was made to interact with the simplest amino acid, glycine. Different model variants were used to highlight the consequences of charge rearrangement and chemical bonds on the time evolution. The charge-rearrangement-enhanced x-ray ionization of molecules effect is also discussed to address the capability of a classical MD based approach, i.e., XMDYN, to capture such a molecular phenomenon.

The solvation structure of CO2 in dichloromethane – A comparative correlated, semi-empirical and classical MD simulation study

In this work the structural and dynamical properties of CO2 in dichloromethane were studied via classical and QMCF MD simulations employing a variety of increasingly complex computational methods, namely correlated resolution-of-identity second-order Møller-Plesset perturbation theory (RI MP2), resolution-of-identity density functional theory (DFT) using the B3LYP functional with and without dispersion correction, semi-empirical self consistent density-functional tight-binding (SCC DFTB) as well as the second-generation geometries, vibrational frequencies, and non-covalent interaction extended tight-binding (GFN2-xTB) approach. All levels of theory yield a similar description of the spherically-shaped first solvation layer found in the range of 6.4 to 6.9 Å. The structural and dynamical data obtained via RI B3LYP-D3 are found in good agreement with the high level RI MP2 reference, whereas the SCC DFTB/3ob and GFN2-xTB methods displayed minor deficiencies in the description of halogen-based interactions. Despite the observed structural differences both the vibrational frequencies of the solute as well as the first shell mean ligand residence times show similar values, pointing towards rapid exchange reactions of first shell ligands with the bulk. In addition several classical potential models for the description of the system have been assessed and adjusted MM potential parameters providing structural and dynamical data comparable to the much more expensive quantum chemical methods are provided.

(Invited) Modeling the Defect Chemistry, Transport Properties, and Stability of Anti-Perovskite Materials

Solid-state electrolytes with fast lithium conduction are the core of the all-solid-state Li-battery technology. By substituting the organic electrolyte with a piece of non-flammable ceramic material, we can achieve better safety, higher specific capacity, and a higher energy density. To date, the major bottleneck for this technology is the slow Li diffusion in the solid-state electrolyte and the interfacial incompatibility between the electrolyte and electrodes. To resolve these issues, several families of fast ionic conductors have been developed. Understanding Li diffusion in these materials is essential to the development of novel family fast ionic conductors. To this end, atomistic modeling provides us with a unique tool to obtain comprehensive information on atom motion, which is difficult to access with experimental techniques. In this talk, we showcase our group’s atomistic simulations regarding a novel family of superionic conductors, Li-rich antiperovskites (LiRAPs)LiRAPs are a promising family of solid electrolytes, which exhibit ionic conductivities above 1 mS/cm at room temperature, among the highest reported values to date. Here, we report on the defect chemistry and the associated lithium transport in Li3OCl, a prototypical LiRAP, using DFT calculations and classical MD simulations [1]. We studied these materials’ phase, interfacial, and voltage stability [2,3] with DFT, showing good agreement with experiments, further proposing low-dimensional superionic antiperovskites [3]. In addition, the interfacial properties were studied for both protonated and fluorinated materials [4]. Analogous simulations were also carried out for Na-rich antiperovskites [5]. Acknowledgments Support from the Research Grants Council of Hong Kong is gratefully acknowledged.

(Digital Presentation) Free Solvent Molecules in the Electrolyte Leading to Severe Safety Concern of Ni-Rich Li-Ion Batteries

The safety of Li-ion batteries is one of the most important factors, if not the most, determining their practical applications. We have found that free carbonate-based solvent molecules in the hybrid electrolyte system can cause severe safety concerns. The 18650 battery cells using the 50% varied-alkyl chain piperidinium-based TFSI result in an immediate and aggressive explosion after applying the impact test (UN38.3) compared with the cell using the conventional electrolyte, having a mild explosion after applying the impact force with 16 s-delayed time. Furthermore, the greater concentration of gases especially C2H4 and CO in the hybrid electrolyte system compared with the conventional electrolyte system was observed by online in situ DEMS, which is evidence for the aggressive explosion of the cell using the hybrid electrolyte. In additionally, the classical MD investigation is suggested that hybrid electrolytes have a high AGG concentration of Li+ and TFSI−, producing a high concentration of the isolated EC or free solvent, which could generate more gases in the fully charged battery cell. Mixing ionic liquids with a carbonate-based solvent as the co-solvent at a fixed salt concentration of 1 M LiPF6 can lead to free carbonate-based molecules causing poor charge storage performance and safety concerns. Keywords: Ni-rich Li-ion bateriesIonic liquids; Safety; Battery explosion; Mismatch electronic properties; 1865 cylindrical cells

Interactions of boron nitride nanosheet with amino acids of differential polarity

Free amino acids represent a category of different biomolecules in the blood plasma, which bond together to make up larger organic molecules such as peptides and proteins. Their interactions with biocompatible nanoparticles are especially important for plasma-related biomedical applications. Among the various nanomaterials, the applications of carbon and boron nitride-based nanotubes/nanosheets have shown a huge increase in recent years. The effect of molecular polarity on the interaction between a boron nitride nanosheet (BNNS) and amino acids is investigated with quantum mechanical calculations by density functional theory (DFT), classical MD simulations, and well-tempered metadynamics simulations. Four representative amino acids, namely, alanine (Ala), a nonpolar amino acid, and aspartic acid (Asp), lysine (Lys) and serine (Ser), three polar amino acids are considered for their interactions with BNNS. In DFT calculations, the values of the adsorption energies for Lys-BNNS and Ser-BNNS complexes are − 48.32 and − 32.89 kJ/mol, respectively, which are more stable than the other cases. Besides, the adsorption energy calculated confirms the exergonic reactions for all investigated systems; it implied that the interaction is favorable electronically. The MD results show that the LYS molecules have a higher attraction toward BNNS because of its alkane tail in its side chain, and the ASP revealed the repulsion force originating from its COO– group. All the results are confirmed by free energy analyzes in which the LYS showed the highest adsorption free energy at a relatively farther distance than other complexes. In fact, our results revealed the contribution of functional groups and backbone of the amino acids in the adsorption or repulsion features of the studied systems.

Diclofenac Ion Hydration: Experimental and Theoretical Search for Anion Pairs.

Self-assembly of organic ions in aqueous solutions is a hot topic at the present time, and substances that are well-soluble in water are usually studied. In this work, aqueous solutions of sodium diclofenac are investigated, which, like most medicinal compounds, is poorly soluble in water. Classical MD modeling of an aqueous solution of diclofenac sodium showed equilibrium between the hydrated anion and the hydrated dimer of the diclofenac anion. The assignment and interpretation of the bands in the UV, NIR, and IR spectra are based on DFT calculations in the discrete-continuum approximation. It has been shown that the combined use of spectroscopic methods in various frequency ranges with classical MD simulations and DFT calculations provides valuable information on the association processes of medical compounds in aqueous solutions. Additionally, such a combined application of experimental and calculation methods allowed us to put forward a hypothesis about the mechanism of the effect of diclofenac sodium in high dilutions on a solution of diclofenac sodium.

Elucidation of the Conformational Transition of Oligopeptidase B by an Integrative Approach Based on the Combination of X-ray, SAXS, and Essential Dynamics Sampling Simulation

Oligopeptidase B (OPB) is the least studied group from the prolyl oligopeptidase family. OPBs are found in bacteria and parasitic protozoa and represent pathogenesis factors of the corresponding infections. OPBs consist of two domains connected by a hinge region and have the characteristics of conformational dynamics, which include two types of movements: the bridging/separation of α/β-hydrolase catalytic and β-propeller-regulatory domains and the movement of a loop carrying catalytic histidine, which regulates an assembly/disassembly of the catalytic triad. In this work, an elucidation of the interdomain dynamics of OPB from Serratia proteamaculans (SpOPB) with and without modification of the hinge region was performed using a combination of X-ray diffraction analysis and small-angle X-ray scattering, which was complemented with an essential dynamics sampling (EDS) simulation. The first crystal structure of catalytically deficient SpOPB (SpOPBS532A) with an intact hinge sequence is reported. Similarly to SpOPB with modified hinges, SpOPBS532A was crystallized in the presence of spermine and adopted an intermediate conformation in the crystal lattice. Despite the similarity of the crystal structures, a difference in the catalytic triad residue arrangement was detected, which explained the inhibitory effect of the hinge modification. The SpOPBS532A structure reconstituted to the wild-type form was used as a starting point to the classical MD followed by EDS simulation, which allowed us to simulate the domain separation and the transition of the enzyme from the intermediate to open conformation. The obtained open state model was in good agreement with the experimental SAXS data.

First biphotochromic fluorescent protein moxSAASoti stabilized for oxidizing environment

Biphotochromic proteins simultaneously possess reversible photoswitching (on-to-off) and irreversible photoconversion (green-to-red). High photochemical reactivity of cysteine residues is one of the reasons for the development of “mox”-monomeric and oxidation resistant proteins. Based on site-saturated simultaneous two-point C105 and C117 mutagenesis, we chose C21N/C71G/C105G/C117T/C175A as the moxSAASoti variant. Since its on-to-off photoswitching rate is higher, off-to-on recovery is more complete and photoconversion rates are higher than those of mSAASoti. We analyzed the conformational behavior of the F177 side chain by classical MD simulations. The conformational flexibility of the F177 side chain is mainly responsible for the off-to-on conversion rate changes and can be further utilized as a measure of the conversion rate. Point mutations in mSAASoti mainly affect the pKa values of the red form and off-to-on switching. We demonstrate that the microscopic measure of the observed pKa value is the C–O bond length in the phenyl fragment of the neutral chromophore. According to molecular dynamics simulations with QM/MM potentials, larger C–O bond lengths are found for proteins with larger pKa. This feature can be utilized for prediction of the pKa values of red fluorescent proteins.

Evidence of a liquid\u2013liquid phase transition in H_2O and D_2O from path-integral molecular dynamics simulations

We perform path-integral molecular dynamics (PIMD), ring-polymer MD (RPMD), and classical MD simulations of H_2O and D_2O using the q-TIP4P/F water model over a wide range of temperatures and pressures. The density rho (T), isothermal compressibility kappa _T(T), and self-diffusion coefficients D(T) of H_2O and D_2O are in excellent agreement with available experimental data; the isobaric heat capacity C_P(T) obtained from PIMD and MD simulations agree qualitatively well with the experiments. Some of these thermodynamic properties exhibit anomalous maxima upon isobaric cooling, consistent with recent experiments and with the possibility that H_2O and D_2O exhibit a liquid-liquid critical point (LLCP) at low temperatures and positive pressures. The data from PIMD/MD for H_2O and D_2O can be fitted remarkably well using the Two-State-Equation-of-State (TSEOS). Using the TSEOS, we estimate that the LLCP for q-TIP4P/F H_2O, from PIMD simulations, is located at P_c = 167 pm 9 MPa, T_c = 159 pm 6 K, and rho _c = 1.02 pm 0.01 g/cm^3. Isotope substitution effects are important; the LLCP location in q-TIP4P/F D_2O is estimated to be P_c = 176 pm 4 MPa, T_c = 177 pm 2 K, and rho _c = 1.13 pm 0.01 g/cm^3. Interestingly, for the water model studied, differences in the LLCP location from PIMD and MD simulations suggest that nuclear quantum effects (i.e., atoms delocalization) play an important role in the thermodynamics of water around the LLCP (from the MD simulations of q-TIP4P/F water, P_c = 203 pm 4 MPa, T_c = 175 pm 2 K, and rho _c = 1.03 pm 0.01 g/cm^3). Overall, our results strongly support the LLPT scenario to explain water anomalous behavior, independently of the fundamental differences between classical MD and PIMD techniques. The reported values of T_c for D_2O and, particularly, H_2O suggest that improved water models are needed for the study of supercooled water.

Addressing Dynamics at Catalytic Heterogeneous Interfaces with DFT-MD: Anomalous Temperature Distributions from Commonly Used Thermostats.

Density functional theory-based molecular dynamics (DFT-MD) has been widely used for studying the chemistry of heterogeneous interfacial systems under operational conditions. We report frequently overlooked errors in thermostated or constant-temperature DFT-MD simulations applied to study (electro)catalytic chemistry. Our results demonstrate that commonly used thermostats such as Nosé–Hoover, Berendsen, and simple velocity-rescaling methods fail to provide a reliable temperature description for systems considered. Instead, nonconstant temperatures and large temperature gradients within the different parts of the system are observed. The errors are not a “feature” of any particular code but are present in several ab initio molecular dynamics implementations. This uneven temperature distribution, due to inadequate thermostatting, is well-known in the classical MD community, where it is ascribed to the failure in kinetic energy equipartition among different degrees of freedom in heterogeneous systems (Harvey et al. J. Comput. Chem.1998, 726−740) and termed the flying ice cube effect. We provide tantamount evidence that interfacial systems are susceptible to substantial flying ice cube effects and demonstrate that the traditional Nosé–Hoover and Berendsen thermostats should be applied with care when simulating, for example, catalytic properties or structures of solvated interfaces and supported clusters. We conclude that the flying ice cube effect in these systems can be conveniently avoided using Langevin dynamics.

Atomistic modeling of the coupling between electric field and bulk plastic deformation in fcc metals

A notable impediment in maintaining high electric fields in accelerating structures is the onset of breakdown events. While bulk mechanical properties of the materials are known to significantly affect the breakdown propensity, the underlying mechanisms coupling electric fields to bulk plastic deformation in experimentally relevant thermal and electrical loading conditions remain to be identified at the atomic scale. We present the results of large-scale molecular dynamics simulations (MD) to investigate a possible mode of coupling. Specifically, we consider the activation of Frank-Read sources, which leads to dislocation multiplication, under the combined action of biaxial thermal stresses caused by rf losses and surface tractions induced by electric fields. With the help of a charge-equilibration formalism incorporated in a classical MD model, we show that the creation of surface slipped steps can couple to electric fields in a way that enhances local stresses and facilitates further activation of existing dislocation sources. We quantify the possible enhancement of surface slip under typical microstructural parameters of annealed copper. We show that such a mechanism could potentially promote breakdown precursor formation at very high electric fields, but that its impact is limited at fields typical of the operation of accelerator structures. In this regime, thermal stresses caused by rf losses are expected to be the main drivers of plastic deformation.

Molecular dynamics simulation, DFT calculations and vibrational spectroscopic study of N[sbnd]H•••O bound dimer models for DL-β-phenylalanine and 3-amino-3-(4-chlorophenyl)propionic acid

Zwitterionic NH•••O bonded dimer structures have been proposed one each for DL-β-Phenylalanine and 3-Amino-3-(4-chlorophenyl)propionic acid. Stable zwitterionic monomer possessing NH3+ and COO¯ moieties in implicit aqueous solvation were computed at B3LYP/6-311++G** level and used for classical MD simulations. MD simulations yielded, among many NH•••O bonded transient dimer and trimer species, the two dimer structures with longest lifetime τ in water medium (τ = 111.67 ps for DL-β-Phenylalanine and 111.53 ps for 3-Amino-3-(4-chlorophenyl)propionic acid). The first peaks in radial distribution functions (RDF) confirmed the formation of NH•••O bonded dimer structures, one each for DL-β-Phenylalanine and 3-Amino-3-(4-chlorophenyl)propionic acid; the first minima determined the cut-off values for the inter-molecular H•••O distances. Further, the first minimum-solvation shell also indicated one zwitterionic dimer structure with 10 water molecules as solvent medium. Experimental IR frequencies due to the NH3+ and COO¯ moieties agree within 5% of the computed values for the dimer structures. Low-frequency Raman bands near 100–50 cm−1 are assigned to the torsional vibration modes of zwitterionic NH•••O bonded dimer structures. On the role of Chlorine with respect to all the molecular properties of 3-Amino-3-(4-chlorophenyl)propionic acid vs DL-β-Phenylalanine computed from NBO, AIM and NCI calculations, its influence is not substantial but discernible enough for gaining insights into the two NH•••O bonded zwitterionic dimer species.

Modeling Substrate Coordination to Zn-Bound Angiotensin Converting Enzyme 2

The Angiotensin Converting Enzyme 2 (ACE2) is a crucial regulator for the renin-angiotensin system. ACE2 converts the Angiotensin (Ang) II peptide into Ang 1–7 and thus promotes various anti-proliferative, anti-inflammatory and cardioprotective effects. In this study, we computationally designed several Ang II mutants to find a strong binding sequence to ACE2 receptor and examined the role of ligand substitution in the docking of native as well as mutant Ang II to the receptor. The peptide in the ACE2-peptide complex was coordinated to zinc (Zn) in the ACE2 cleft. The MD-generated root-mean-square deviation values were mostly similar between the native and mutant peptides considered in this work. The initial peptide-ACE2 poses were generated by molecular docking. The MD simulations used were post-processed by MM-PBSA to generate the binding free energies. All of the peptides studied here demonstrated negative binding free energies, which suggest that all the tested peptides form stable complexes with ACE2. Additionally, by examining the trends in the binding free energies calculated with different internal dielectric constants, it is evident that native Ang II and two of its variants have strongest binding to ACE2 receptor. Even though free energy measurements through classical MD simulation have certain limitations, in the absence of the availability of crystal structures of ACE2-peptide complexes, our work provides some structural insights for various Ang II analogs and how they may interact with a zinc atom within the active site of the enzyme.

Effect of lubricants on the rotational transmission between solid-state gears.

Lubricants are widely used in macroscopic mechanical systems to reduce friction and wear. However, on the microscopic scale, it is not clear to what extent lubricants are beneficial. Therefore, in this study, we consider two diamond solid-state gears at the nanoscale immersed in different lubricant molecules and perform classical MD simulations to investigate the rotational transmission of motion. We find that lubricants can help to synchronize the rotational transmission between gears regardless of the molecular species and the center-of-mass distance. Moreover, the influence of the angular velocity of the driving gear is investigated and shown to be related to the bond formation process between gears.

A doxorubicin-peptide-gold nanoparticle conjugate as a functionalized drug delivery system: exploring the limits.

Efficient transport of pharmaceuticals to malignant cells in the human body often requires the application of drug-delivery systems (DDSs) consisting of several building blocks, each of them bearing a specific function. While nanoparticles are promising as potential carrier moieties, biomolecules may add to the efficient delivery by binding several drug molecules simultaneously. In this contribution, we apply a combination of atomistic molecular dynamics simulations and density functional theory calculations to characterize a multi-component DDS for the transport of the anthracycline antibiotic doxorubicin (DOX), comprising a gold nanoparticle (NP) and a drug-binding peptide (DBP) grafted on the NP surface. We have shown previously that the DDS can stabilize one DOX per DBP. However, by increasing the drug load to a 2 : 1 DOX : DBP ratio the two drug molecules compete for the available adsorption sites, which may cause spontaneous dissociation of one DOX molecule. We identify the chain length of the DBP as a limiting factor for the drug-loading capacity and provide important guidelines for further optimization of multi-component functionalized DDSs.

Atomic mass dependence of the nuclear quantum effect in NH4+(H2O)

• Path integral molecular dynamics (PIMD) was used to treat the nuclear quantum effect. • The ammonium cluster has two competing quantum effects. • The quantum fluctuation along the covalent bond strengthens the intermolecular interaction. • The quantum fluctuation along of bond angle decreases intermolecular interaction. The interaction between ammonium ions and water has been studied previously via molecular dynamics. However, the nuclear quantum effect phenomenon did not receive sufficient consideration therein. In this study, we report the ab initio path integral molecular dynamics (PIMD) simulations of the isotopologues of NH 4 + ( H 2 O ) , that is, NH 4 + ( H 2 O ) , ND 4 + ( D 2 O ) , and NT 4 + ( T 2 O ) , as well as the classical MD simulations. We found that the intermolecular distance does not change monotonically. Even though the nuclear quantum effect shortens the overall intermolecular distance (N–O atoms), the distance for NH 4 + ( H 2 O ) is longer than that for NT 4 + ( T 2 O ) . Two dimensional distributions of the binding energies with the contour lines were constructed to assess this unusual quantum behavior. We find that the elongation of the covalent bond increases the binding energy, while the quantum fluctuation of the O–N–H b bond angle decreases it. The bond length is determined by the delicate balance of such competing quantum effects.