Integral Molecular Dynamics Simulations Research Articles

Impact of Nuclear Quantum Effects on the Structural Properties of Protonated Water Clusters.

Nuclear quantum effects (NQEs) play a crucial role in hydrogen-bonded systems due to quantum tunneling and proton fluctuation. Our understanding of how NQEs affect microstructures mainly focuses on bulk phases of liquids and solids but remains deficient for water clusters, including their hydrogen nuclei, hydrogen-bonded configurations, and temperature dependence. Here, we conducted ab initio molecular dynamics (MD) and path integral MD simulations to investigate the influence of NQEs on the structural properties of protonated water clusters H+(H2O)n (n = 3, 6, 9, 12). The results reveal that the NQEs become less evident as the cluster size increases due to the competition between NQEs and electrostatic interactions. Simulations of several H+(H2O)6 isomers at different temperatures indicate that the effect of elevated temperature on proton transfer is related to the initial structure. Interestingly, the process of proton transfer also involves the interconversion between Zundel-type and Eigen-type isomers. These findings significantly deepen our understanding of ion-water and water-water interactions, opening new avenues for the study of hydrated ion clusters and related systems.

The Binding of Remdesivir to SARS-CoV-2 RNA-Dependent RNA Polymerase May Pave The Way Towards the Design of Potential Drugs for COVID-19 Treatment.

We seek to provide an understanding of the binding mechanism of Remdesivir, as well as structural and conformational implications on SARS-CoV-2 virus RNA-dependent RNA polymerase upon its binding and identify its crucial pharmacophoric moieties. The coronavirus disease of 2019 (COVID-19) pandemic had infected over a million people, with 65,000 deaths as of the first quarter of 2020. The current limitation of effective treatment options with no approved vaccine or targeted therapeutics for the treatment of COVID-19 has posed serious global health threats. This has necessitated several drug and vaccine development efforts across the globe. To date, the farthest in the drug development pipeline is Remdesivir. We performed the molecular dynamics simulation, quantified the energy contributions of binding site residues using per-residue energy decomposition calculations, and subsequently generated a pharmacophore model for the identification of potential SARS-CoV-2 virus RNA-dependent RNA polymerase inhibitors. Integrative molecular dynamics simulations and thermodynamic calculations coupled with advanced post-molecular dynamics analysis techniques were employed. Our analysis showed that the modulatory activity of Remdesivir is characterized by an extensive array of high-affinity and consistent molecular interactions with specific active site residues that anchor Remdemsivir within the binding pocket for efficient binding. These residues are ASP452, THR456, ARG555, THR556, VAL557, ARG624, THR680, SER681, and SER682. Results also showed that Remdesivir binding induces minimal individual amino acid perturbations, subtly interferes with deviations of C-α atoms, and restricts the systematic transition of SARS-CoV-2 RNA-dependent RNA polymerase from the "buried" hydrophobic region to the "surface-exposed" hydrophilic region. We also mapped a pharmacophore model based on the observed high-affinity interactions with SARSCoV- 2 virus RNA-dependent RNA polymerase, which showcased the crucial functional moieties of Remdesivir and was subsequently employed for virtual screening. The structural insights and the provided optimized pharmacophoric model would augment the design of improved analogs of Remdesivir that could expand treatment options for COVID-19.

Orientation and Conformation of Proteins at the Air-Water Interface Determined from Integrative Molecular Dynamics Simulations and Sum Frequency Generation Spectroscopy.

Understanding the assembly of proteins at the air-water interface (AWI) informs the formation of protein films, emulsion properties, and protein aggregation. Determination of protein conformation and orientation at an interface is difficult to resolve with a single experimental or simulation technique alone. To date, the interfacial structure of even one of the most widely studied proteins, lysozyme, at the AWI remains unresolved. In this study, molecular dynamics (MD) simulations are used to determine if the protein adopts a side-on, head-on, or axial orientation at the AWI with two different forcefields, GROMOS-53a6 + SPC/E and a99SB-disp + TIP4P-D. Vibrational sum frequency generation (SFG) spectroscopy experiments and spectral SFG calculations validate consistency between the structure determined from MD and experiments. Overall, we show with strong agreement that lysozyme adopts an axial conformation at pH 7. Further, we provide molecular-level insight as to how pH influences the binding domains of lysozyme resulting in side-on adsorption near the isoelectric point of the lysozyme.

In Silico Repurposing of J147 for Neonatal Encephalopathy Treatment: Exploring Molecular Mechanisms of Mutant Mitochondrial ATP Synthase.

Neonatal Encephalopathy (NE) is a mitochondrial ATP synthase (mATPase) disease, which results in the death of infants. The case presented here is reportedly caused by complex V deficiency as a result of mutation of Arginine to Cysteine at residue 329 in the mATPase. A recent breakthrough was the discovery of J147, which targets mATPase in the treatment of Alzheimer's disease. Based on the concepts of computational target-based drug design, this study investigated the possibility of employing J147 as a viable candidate in the treatment of NE. The structural dynamic implications of this drug on the mutated enzyme are yet to be elucidated. Hence, integrative molecular dynamics simulations and thermodynamic calculations were employed to investigate the activity of J147 on the mutated enzyme in comparison to its already established inhibitory activity on the wild-type enzyme. A correlated structural trend occurred between the wild-type and mutant systems whereby all the systems exhibited an overall conformational transition. Equal observations in favorable free binding energies further substantiated uniformity in the mobility, and residual fluctuation of the wild-type and mutant systems. The similarity in the binding landscape suggests that J147 could as well modulate mutant mATPase activity in addition to causing structural modifications in the wild-type enzyme. Findings suggest that J147 can stabilize the mutant protein and restore it to a similar structural state as the wild-type which depicts functionality. These details could be employed in drug design for potential drug resistance cases due to mATPase mutations that may present in the future.

The Influences of Drug-Resistant Mutations of EGFR to the Inhibitor Binding Affinity and the Drug Target Selectivity Profiles

Small molecular inhibitors of receptor kinases suppress cellular signaling pathways mediated by the proteins that lead to malignant cell growth and division. We have studied molecular interactions between epidermal grow factor receptor (EGFR) and the small molecular inhibitors targeting the protein, using free energy molecular dynamics (MD) simulations. First we quantified the influence of a mutation (T790M) known to cause drug-resistance. After prolonged application of an inhibitor, cancer cells begin to express the drug-resistant somatic mutation that reduces the efficacy of the EGFR selective inhibitors. Using thermodynamic integration MD simulations, we show that the mutation (T790M) reduces the binding affinity of several reversible inhibitors of EGFR to the enzymatically active conformation of the protein. Metadynamics MD simulations of WT and mutant EGFRs in apo show that the mutation causes a conformational equilibrium shift toward the active conformation. The binding energy penalty to the active conformation and the equilibrium shift toward the active state explain the observed dissociation constant profile of gefitinib. Second, we quantified the target selectivity of the EGFR inhibitors. Based on a series of metadynamics MD simulations of EGFRs bound to gefitinib, we demonstrate that the inhibitor recognizes both the active and the Src/Cdk-like inactive conformations. The results agree well with a recent crystallographic study that showed gefitinib interacts with the inactive conformation of the T790M/L858R dual mutant EGFR. These computational results provide fine details of the inhibitor-protein interactions, which will guide further development of the receptor kinase inhibitors.

Path Integral Molecular Dynamics Simulation on Atomic Distribution in Amorphized Ice Ic

We have investigated the effects of compression and quantization on atomic distribution in ice Ic and in its compressed states at 77 K and 10 K, using the path integral molecular dynamics (PIMD) simulations over wide range of volume. It has been found that the high density amorphous ice (HDA) is attained by compression but volume range to retain ice structure is wider at 10 K than 77 K. We have discovered that quantum dispersion of atoms in ice Ic at 10 K induces non-zero probability that hydrogen-bonded H2O molecular molecules are oriented nonlinearly in the crystal structure, which was believed to contain exclusively linear orientation of hydrogen-bonded molecular pairs in this ice. It has been found that for HDA there is each non-zero probability of orientational disorder of hydrogen-bonded H2O pairs, of such uniform distribution of H atoms as observed in supercritical fluids in general, and of H atoms located at the O-O midpoint. The present PIMD simulations have revealed that these observed anomalous characteristics of atomic distribution in HDA are caused by both quantization of atoms and compression of the system.

Nuclear quantum effects in a 1-D model of hydrogen bonded ferroelectrics

A one dimensional model of a coupled hydrogen (H) bonding chain is developed and parametrized to density functional theory (DFT) calculations on squaric acid, a prototypical H-bonded antiferroelectric crystal. The energetics of single and collective proton jumps and its dependence on H-bond length, as obtained by DFT, is reproduced quite well in the model despite its simplicity where only hydrogen and oxygen atom positions in (O-H...O) H-bonds and nearest-neighbor coupling between H positions are explicitly included. Classical and path- integral molecular dynamics simulations are performed to shed light on nuclear quantum effects and how they influence the paraelectric phase transition. A large H/D isotope shift in the transition temperature TC as well as a geometric isotope effect is obtained in good agreement with experiment. Fixing the O-O bond length results in shifts of TC to higher temperature but a pronounced isotope shift of TC remains, highlighting the importance of quantum effects beyond the geometrical changes in H-bonds accompanying isotopic substitution. Intermediate between fully atomistic models and simpler Ising-type models, the proposed H-bond chain model is a useful toy model for investigating microscopic mechanisms behind phase transitions in H-bonded ferroelectrics and the detailed role of quantum fluctuations.

Quantum simulation for muoniated and deuterated methyl radicals in implicit water solvent: combined ab initio path integral molecular dynamics and the polarizable continuum model simulation study

We have combined ab initio path integral molecular dynamics (PIMD) simulation and the polarizable continuum model (PCM) method to efficiently incorporate solvent effects into nuclear quantum fluctuation of molecular systems. Our combined ab initio PIMD–PCM simulation was applied to muoniated and deuterated methyl radical immersed in implicit water solvent to gain information on solvent and isotope effects from one simulation run. We found that solvent effects lead to the bond elongation and a decrease in the magnitude of isotropic hyperfine coupling constants. These are consistent with the trends in conventional static calculations and experiments. In addition, the performance of cavity models (universal force field, united atom specified for Kohn–Sham and these hybrid models) and the conservation of the PIMD–PCM Hamiltonian were accessed. We confirmed that solvent effects on nuclear quantum fluctuation are efficiently computed using our combined simulation of quantum solute in implicit solvent.

Muon-Electron Hyperfine Coupling Constants of Muoniated Ethyl Radical: A Path Integral Simulation Study with Semiempirical Molecular Orbital Method

We have investigated, by on-the-fly path integral molecular dynamics (PIMD) simulations, which can take into account the nuclear quantum and thermal effects, the nuclear quantum effect on the muoniated ethyl radical, where one of the hydrogen atoms of the methyl group in the ethyl radical is substituted with a muonium. Muonium consists of a positive muon and an electron, which can be considered as an ultra-light isotope of a hydrogen atom, and we here focused on the muon spin resonance/rotation/relaxation (μSR) and the hyperfine coupling constants (HFCC). Our PIMD simulation with the semiempirical PM6 method has succeeded in treating the nuclear quantum effect, which results mainly in the elongation of the bond length and the characteristic rotation of the CH2Mu group. Our PIMD simulation provides dramatic improvements in the characteristics of the HFCCs obtained from the conventional PM6 calculation, although the calculated HFCCs are not in qualitative agreement with the corresponding experimental ones because of the limitation of the semiempirical PM6 method for systems with an unpaired electron.

Semiempirical investigations on the stabilization energies and ionic hydrogen-bonded structures of F−(H2O) n and Cl−(H2O) n (n = 1–4) clusters

Abstract Several semiempirical methods were utilized to analyze the structures and stabilities of X −(H2O) n (X = F, Cl; n = 1–4) clusters with respect to the number of water molecules through their comparison with ab initio molecular orbital calculations. Our results show that the recently developed PM6-DH+ semiempirical method can provide reasonable binding energies of hydrated fluoride and chloride ion clusters, which are consistent with the corresponding experimental results. For the optimized geometries of X = F, however, the semiempirical methods show that the global minima are close to HF(OH)−(H2O) n−1 structures, which are different from the ab initio calculations. Meanwhile, the topological characteristics for the global minima of X = Cl obtained by semiempirical methods have the same symmetries with ab initio calculations. All calculation levels agree on the trend of decreasing ion-water interaction with the increasing number of water molecules. We also found a new structure of Cl−(H2O)4 with a second hydration shell as a complement of previous studies. Those are very important data for our near-future study of on-the-fly semiempirical molecular dynamics (MD) or path integral MD simulation. PACS 36.40.Mr, 31.15.bu, 31.15.A-

Quantum phase transition of water clusters: molecular dynamics simulations with a model potential

We have performed molecular dynamics (MD) simulations on water octamer clusters with a model potential (SPC/F 2). In addition to classical MD simulations, path integral MD simulations are performed to study quantum effects in the phase transitions of the system. Replica exchange method is used for efficient canonical samplings. Order parameters at various temperatures are calculated by classical and quantum simulations, respectively. It is found that the cluster exhibits quantum behavior in phase transitions around 100 K. The phase transition temperature is found to be lower by 25 K for quantum simulations, compared to the classical simulations.

Ab initio molecular dynamics study of crystal hydrates of HCl including path integral results

The hydrates of hydrogen chloride are ionic crystals, which contain hydronium. The hydronium in the monohydrate has been reported to be statistically disordered between two possible sites related by inversion symmetry. Abinitio molecular dynamics (MD) calculations are presented for the mono-, di- and tri-hydrates of hydrogen chloride using the density functional based Car–Parrinello technique. The simulations were carried out with the goal of investigating proton disorder in these crystals. The possible role of nuclear quantum effects has been explored via path integral MD simulations. The results suggest that the proposed disordered sites in the monohydrate are dynamically unstable and therefore unlikely to be responsible for the reported disorder. Unfortunately, little information was obtained for the dihydrate because the large unit cell leads to difficulties in carrying out the simulations. Nuclear quantum effects are shown to be important for characterizing the proton distributions in the trihydrate.