Molecular Energy Calculations Research Articles

Molecular Docking and Dynamic Simulation Studies of Benzoylated Emodin into HBV Core Protein

Objective: The hepatitis B virus (HBV) core protein was chosen as receptor target for a new, selective and effective due to resistance of current hepatitis B drugs against reverse transcriptase. It forms the capsid of viral particles and essential for viral genome DNA replication and maturation. Emodin was known showing inhibitory effect on HBV replication weakness, but persistent both in vitro and in vivo so still need modification. In this study, emodin derivatives were conducted as an inhibitor candidate of capsid assembly by disruption formation dimer-dimer HBV core protein using molecular docking and dynamic simulation. Methods: Structure-based virtual docking approach was used to design of benzoylated emodin derivatives into HBV core protein as receptor using Molegro Virtual Docker 6.0 program. The stability of interacting residues of proteins with compounds was identified via molecular dynamics and free binding energy calculations using Amber 12. Results: The ligand binding site in an HBV core protein was an interfacial hydrophobic pocket and placed at the dimer-dimer of the core protein interface. Interactions between emodin and derivatives indicated by hydrogen bonding and steric interaction between the ligand with the amino acid residues in the HBV core protein. It is predicted that viral replication would inhibit due to a change in orientation of capsid assembly by core proteins. The benzoylated emodin derivatives showed promising inhibitory profiles better than emodin which were indicated by their binding scores were more negative. Conclusion: This study provides a basis for further chemical design for more effective derivatives of emodin derivatives. Key words: Hepatitis B virus core protein, Molecular docking, Dynamic, Emodin.

Dissociation Energy of the Hydrogen Molecule at 10^{-9} Accuracy.

The ionization energy of ortho-H_{2} has been determined to be E_{I}^{o}(H_{2})/(hc)=124 357.238 062(25) cm^{-1} from measurements of the GK(1,1)-X(0,1) interval by Doppler-free, two-photon spectroscopy using a narrow band 179-nm laser source and the ionization energy of the GK(1,1) state by continuous-wave, near-infrared laser spectroscopy. E_{I}^{o}(H_{2}) was used to derive the dissociation energy of H_{2}, D_{0}^{N=1}(H_{2}), at 35 999.582 894(25) cm^{-1} with a precision that is more than one order of magnitude better than all previous results. The new result challenges calculations of this quantity and represents a benchmark value for future relativistic and QED calculations of molecular energies.

Cation-dependent conformations in 25-hydroxyvitamin D3-cation adducts measured by ion mobility-mass spectrometry and theoretical modeling

Ion mobility-mass spectrometry is a useful tool in separation of biological isomers, including clinically relevant analytes such as 25-hydroxyvitamin D3 (25OHD3) and its epimer, 3-epi-25-hydroxyvitamin D3 (epi25OHD3). Previous research indicates that these epimers adopt different gas-phase sodiated monomer structures, either the “open” or “closed” conformer, which allow 25OHD3 to be readily resolved in mixtures. In the current work, alternative metal cation adducts are investigated for their relative effects on the ratio of “open” and “closed” conformers. Alkali and alkaline earth metal adducts caused changes in the 25OHD3 conformer ratio, where the proportion of the “open” conformer generally increases with the size of the metal cation in a given group. As such, the ratio of the “open” conformer, which is unique to 25OHD3 and absent for its epimer, can be increased from approximately 1:1 for the sodiated monomer to greater than 8:1 for the barium adduct. Molecular modeling and energy calculations agree with the experimental results, indicating that the Gibbs free energy of conversion from the “closed” to the “open” conformation decreased with increasing cation size, correlating with the variation in ratio between the conformers. This work demonstrates the effect of cation adducts on gas-phase conformations of small, flexible molecules and offers an additional strategy for resolution of clinically relevant epimers.

Microtubule assembly governed by tubulin allosteric gain in flexibility and lattice induced fit

Microtubules (MTs) are key components of the cytoskeleton and play a central role in cell division and development. MT assembly is known to be associated with a structural change in [Formula: see text]-tubulin dimers from kinked to straight conformations. How GTP binding renders individual dimers polymerization-competent, however, is still unclear. Here, we have characterized the conformational dynamics and energetics of unassembled tubulin using atomistic molecular dynamics and free energy calculations. Contrary to existing allosteric and lattice models, we find that GTP-tubulin favors a broad range of almost isoenergetic curvatures, whereas GDP-tubulin has a much lower bending flexibility. Moreover, irrespective of the bound nucleotide and curvature, two conformational states exist differing in location of the anchor point connecting the monomers that affects tubulin bending, with one state being strongly favored in solution. Our findings suggest a new combined model in which MTs incorporate and stabilize flexible GTP-dimers with a specific anchor point state.

Taxifolin as dual inhibitor of Mtb DNA gyrase and isoleucyl-tRNA synthetase: in silico molecular docking, dynamics simulation and in vitro assays.

DNA gyrase and aminoacyl-tRNA synthetases are two essential bacterial enzymes involved in DNA replication, transcription and translation. Flavonoids are plant secondary metabolites with variable phenolic structures. In this study, eight flavonoids structurally similar to quercetin were selected and their ADMET properties were evaluated. Molecular docking and free energy calculations were carried out to examine the binding of these flavonoids to the ATP-binding site and editing domain of DNA gyrase and Isoleucyl-tRNA synthetase, respectively. Taxifolin was found out to be the top lead molecule in both the docking studies with a good number of interactions with the active site amino acids. Further, binding of taxifolin to the proteins was extensively studied using 50ns molecular dynamics simulation. In vitro anti-tuberculosis activity of taxifolin was evaluated and compared with the standard drugs. Minimal inhibition concentration of taxifolin was found to be ≤ 12.5μg/ml.

Molecular excited states from the SCAN functional

ABSTRACTThe performance of the strongly constrained and appropriately normed (SCAN) meta-generalised gradient approximation exchange–correlation functional is investigated for the calculation of time-dependent density-functional theory molecular excitation energies of local, charge-transfer and Rydberg character, together with the excited potential energy curve in H2. The SCAN results frequently resemble those obtained using a global hybrid functional, with either a standard or increased fraction of exact orbital exchange. For local excitations, SCAN can exhibit significant triplet instability problems, resulting in imaginary triplet excitation energies for a number of cases. The Tamm–Dancoff approximation offers a simple approach to improve the situation, but the excitation energies are still significantly underestimated. Understanding the origin of these (near)-triplet instabilities may provide useful insight into future functional development.

Interaction of microtubule depolymerizing agent indanocine with different human αβ tubulin isotypes.

Tubulin isotypes are known to regulate the stability and dynamics of microtubules, and are also involved in the development of resistance against microtubule-targeted cancer drugs. Indanocine, a potent microtubule depolymerizing agent, is highly active against multidrug-resistant (MDR) cancer cells without affecting normal cells. It is known to disrupt microtubule dynamics in cells and induce apoptotic cell death. Indanocine is reported to bind to tubulin at the colchicine site i.e. at the interface of αβ tubulin heterodimer. However, it’s precise binding mode, involved molecular interactions and the binding affinities with different αβ-tubulin isotypes present in MDR cells are not well understood. Here, the binding affinities of human αβ-tubulin isotypes with indanocine were examined, employing the molecular modeling approach i.e. docking, molecular dynamics simulation and binding energy calculations. Multiple sequence analysis suggests that the amino acid sequences are different in the indanocine binding pockets of βI, βIIa, βIII and βVI isotypes. However, such differences are not observed in the amino acid sequences of βIVa, βIVb, and βV tubulin isotypes at indanocine binding pockets. Docking and molecular dynamics simulation results show that indanocine prefers the interface binding pocket of αβIIa, αβIII, αβIVb, αβV, and αβVI tubulin isotypes; whereas it is expelled from the interface binding pocket of αβIVa and αβI-tubulin isotypes. Further, binding free energy calculations show that αβVI has the highest binding affinity and αβI has the lowest binding affinity for indanocine among all β-tubulin isotypes. The binding free energy decreases in the order of αβVI > αβIVb > αβIIa > αβIII > αβV > αβIVa > αβI. Thus, our study provides a significant understanding of involved molecular interactions of indanocine with tubulin isotypes, which may help to design potent indanocine analogues for specific tubulin isotypes in MDR cells in future.

Multicomponent cyclodextrin system for improvement of solubility and dissolution rate of poorly water soluble drug

The purpose of the present study was to investigate the interaction of Cinnarizine (CIN) with Hydroxypropyl-β-Cyclodextrin (HPβCD) in the presence of Hydroxy Acids (HA). Various binary and ternary systems of CIN with HPβCD and HA were prepared by kneading and coevaporation methods. For the ternary systems, HA were tried in three different concentrations. The interaction in solution phase was studied in detail by the phase solubility method, and the solid phase interactions were characterized by Fourier Transform Infrared (FTIR) spectroscopy, Differential Scanning Calorimetry (DSC), X-Ray Diffractometry (XRD), Scanning Electron Microscopy (SEM) and Proton Nuclear Magnetic Resonance (1H-NMR). Phase solubility revealed the positive effect of HA on the complexation of CIN with HPβCD. Solid phase characterization confirmed the formation of inclusion complex in the ternary systems. Solubility and dissolution studies illustrated that out of three different concentrations tried, HA were most effective at the 1 M concentration level. Ternary systems were very effective in improving the solubility as well as dissolution profile of CIN than the CIN–HPβCD binary systems. FTIR, 1H-NMR and Molecular docking studies gave some insight at molecular level that actually which part of CIN was interacting with the HPβCD. Molecular docking and free energy calculation even enlighten the role of tartaric acid in increasing solubility of CIN in the ternary system.

Computer aided drug design using virtual screening and molecular energy calculation of a specific neurodegenerative diseases

Computer-aided drug design (CADD) is designing a drug with the help of computational algorithms. Information technology advances to creates the structure of molecules, molecular modeling and calculate the binding energies of the drug to initiate a new medicine against neurodegenerative diseases. In our work, we implemented virtual screening of a drug-protein interaction is selected from drug data bank with potential drug bank inhibitory activity for a specific neurodegenerative disease. Here we analyze technical CADD studies of the neurodegenerative diseases. Finally selecting the best alkaloid for a specific neurodegenerative disease and predicting the efficiency using computation of alkaloid with molecular energy.

Free-Energy-Based Protein Design: Re-Engineering Cellular Retinoic Acid Binding Protein II Assisted by the Moveable-Type Approach.

How to fine-tune the binding free energy of a small-molecule to a receptor site by altering the amino acid residue composition is a key question in protein engineering. Indeed, the ultimate solution to this problem, to chemical accuracy (±1 kcal/mol), will result in profound and wide-ranging applications in protein design. Numerous tools have been developed to address this question using knowledge-based models to more computationally intensive molecular dynamics simulations-based free energy calculations, but while some success has been achieved there remains room for improvement in terms of overall accuracy and in the speed of the methodology. Here we report a fast, knowledge-based movable-type (MT)-based approach to estimate the absolute and relative free energy of binding as influenced by mutations in a small-molecule binding site in a protein. We retrospectively validate our approach using mutagenesis data for retinoic acid binding to the Cellular Retinoic Acid Binding Protein II (CRABPII) system and then make prospective predictions that are borne out experimentally. The overall performance of our approach is supported by its success in identifying mutants that show high or even sub-nano-molar binding affinities of retinoic acid to the CRABPII system.

Computer Simulations Reveal a Novel Blocking Mode of the hERG Ion Channel by the Antiarrhythmic Agent Clofilium.

The binding modes of many hERG ion channel blockers are well understood, but a notable exception is clofilium, a potent antiarrhythmic agent whose action relies on blocking the current mediated by hERG. From the previously hypothesized binding modes of clofilium to hERG, only two can explain most of the experimental results. In this study, computer simulations are performed in order to analyze the hypothesized binding modes and to identify the consensus one. This is accomplished by employing molecular dynamics (MD) simulations and interaction energy calculations. The results show an unexpected binding mode, in which the quaternary nitrogen is placed in the upper part of the inner cavity, interacting strongly with Ser624, while the chlorophenyl group is located in the lower part, in better agreement with previous experimental results. This novel binding position also explains the higher affinity of clofilium for the related hEag1 channel and was correlated with the possibility that potent hERG blockers interact in specific ways with the residues near the intracellular activation gate, offering a new explanation that could help predict the potency of other hERG-blocking compounds.

Phytosterol Recognition via Rationally Designed Molecularly Imprinted Polymers

Molecularly imprinted polymers (MIPs) prepared via a semi-covalent imprinting strategy using stigmasteryl methacrylate as a polymerisable template have been evaluated by static binding methods for their ability to selectively capture other valuable phytosterol targets, including campesterol and brassicasterol. Design criteria based on molecular modelling procedures and interaction energy calculations were employed to aid the selection of the co-monomer type, as well as the choice of co-monomer:template ratios for the formation of the pre-polymerisation complex. These novel hybrid semi-covalently imprinted polymers employed N,N′-dimethylacryl-amide (N,N′-DMAAM) as the functional co-monomer and displayed specific binding capacities in the range 5.2–5.9 mg sterol/g MIP resin. Their binding attributes and selectivities towards phytosterol compounds were significantly different to the corresponding MIPs prepared via non-covalent procedures or when compared to non-imprinted polymers. Cross-reactivity studies using stigmasterol, ergosterol, cholesterol, campesterol, and brassicasterol as single analytes revealed the importance of the A-ring C-3-β-hydroxyl group and the orientational preferences of the D-ring alkyl chain structures in their interaction in the templated cavity with the N,N′-dimethylamide functional groups of the MIP. Finally, to obtain useful quantities of both campersterol and brassicasterol for these investigations, improved synthetic routes have been developed to permit the conversion of the more abundant, lower cost stigmasterol via a reactive aldehyde intermediate to these other sterols.

Performance of Preformed Au/Cu Nanoclusters Deposited on MgO Powders in the Catalytic Reduction of 4-Nitrophenol in Solution.

The deposition of preformed nanocluster beams onto suitable supports represents a new paradigm for the precise preparation of heterogeneous catalysts. The performance of the new materials must be validated in model catalytic reactions. It is shown that gold/copper (Au/Cu) nanoalloy clusters (nanoparticles) of variable composition, created by sputtering and gas phase condensation before deposition onto magnesium oxide powders, are highly active for the catalytic reduction of 4-nitrophenol in solution at room temperature. Au/Cu bimetallic clusters offer decreased catalyst cost compared with pure Au and the prospect of beneficial synergistic effects. Energy-dispersive X-ray spectroscopy coupled with aberration-corrected scanning transmission electron microscopy imaging confirms that the Au/Cu bimetallic clusters have an alloy structure with Au and Cu atoms randomly located. Reaction rate analysis shows that catalysts with approximately equal amounts of Au and Cu are much more active than Au-rich or Cu-rich clusters. Thus, the interplay between the Au and Cu atoms at the cluster surface appears to enhance the catalytic activity substantially, consistent with model density functional theory calculations of molecular binding energies. Moreover, the physically deposited clusters with Au/Cu ratio close to 1 show a 25-fold higher activity than an Au/Cu reference sample made by chemical impregnation.

Interaction of Snare Mimetic Peptides with Lipid Bilayers

The coiled-coil forming peptides, ‘K’ (KIAALKE)3 and ‘E’ (EIAALEK)3 represent a minimal model for the action of SNARE proteins. Their action on the membrane is typically pictured as a zipper-like closing of the coiled-coil, bringing the membranes into close proximity. However, the individual peptides are significantly less ordered in solution and peptide K has been shown to interact with the membrane. Thus, the real coiled-coil assembly process is likely to be less straightforward and will possess different free energy contributions related to helix folding, coiled-coil assembly and competing interactions with the membrane. To investigate these different factors, we perform molecular simulations and free energy calculations. We use all atom simulations to characterize the interactions of the peptides with lipid bilayers and to analyze the effect of bilayer composition, peptide secondary structure, and the presence of additional residues often found at the peptide terminals. The potentials of mean force (PMF) for bringing the peptides to the bilayer surface are calculated for two bilayer compositions used experimentally: A neutral bilayer containing bulky PC head-groups, and a charged bilayer containing PG lipids. The PMF profiles show minima for the interactions with the PG bilayers, whereas the bulkier PC head groups present a considerable barrier for embedding the peptide in the membrane, and the results are strongly dependent on the peptide secondary structure. To clarify the different free energy contributions to coiled-coil formation, a series of Metadynamics simulations are conducted which analyze the stability of the alpha helical structure in solution, close to the bilayer and in the folded coiled coil. The energy contributions obtained from these all atom simulations can be used to obtain an optimized coarse grained-model for membrane fusion.

Rovibrational spectrum calculations of four electronic states in carbon monoxide molecule: Comparison of two effect correction methods

Accurate calculation of molecular energy is of great significance for studying molecular spectral properties. In this work, the potential energy curve and rovibrational spectrum (Gν) of the ground state X1∑+ and the excited states a3Π, a'3∑+ and A1Π of carbon monoxide molecule are calculated by the multi-reference configuration interaction method. In the calculation, the core-valence correlation correction (CV) effect and scalar relativistic (SR) effect are included.In order to obtain an accurate energy of molecule, two computational schemes are adopted. In the first scheme, i.e. (m MRCI+Q/CBS(TQ5)+CV+SR), the molecular orbital wavefunction is obtained from the Hartree-Fock self-consistent field method by using the basis set aug-cc-pVnZ. The wavefunction is first calculated by the state-averaged complete active space self-consistent field approach. Then the multi-reference configuration interaction method (MRCI) is adopted to calculate the dynamic correlation energy in the potential energy curve. Finally, we use the basis set cc-pCVQZ and aug-cc-pVQZ to calculate the CV effect and SR effect by the MRCI method. In the second scheme (aug-cc-pwCVnZ-DK (n=T, Q, 5)), the potential energy curves (PECs) of these four electronic states are calculated by the MRCI method whose basis set (aug-cc-pwCVnZ-DK) contains the CV effect and SR effect. Finally, in order to reduce the error caused by the basis set, we extrapolate the basis sets of the two computational schemes to the complete basis set. On the basis of the PECs plotted by the different methods, we obtain the spectroscopic parameters of the X1∑+, a3Π, a'3∑+ and A1Π states of the carbon monoxide by solving the internuclear Schrödinger equations through utilizing the numerical integration program “LEVEL”.In this paper, we calculate the SR effect and the CV effect by using different schemes, and the latter is indispensable for accurately calculating the molecular structure. For the lowest two electronic states, we consider the dependence of the two effects on the calculation of the Gaussian basis group (Method B), and find that the accuracy of the rovibrational spectrum is improved. It can be seen that these electronic states have higher requirements for electronic correlation calculation. For higher electronic states, the electron cloud distribution is relatively loose, and the electronic correlation obtained by a single Gaussian basis group can achieve the corresponding calculation accuracy. Of course, since the calculation of the rovibrational spectra is essentially only the relative energy, the offset effect of the electronic correlation effect of different electronic states is also included here in this paper.

Non-branched β-1,3-glucan oligosaccharides trigger immune responses in Arabidopsis.

Fungal cell walls, which are essential for environmental adaptation and host colonization by the fungus, have been evolutionarily selected by plants and animals as a source of microbe-associated molecular patterns (MAMPs) that, upon recognition by host pattern recognition receptors (PRRs), trigger immune responses conferring disease resistance. Chito-oligosaccharides [β-1,4-N-acetylglucosamine oligomers, (GlcNAc)n ] are the only glycosidic structures from fungal walls that have been well-demonstrated to function as MAMPs in plants. Perception of (GlcNAc)4-8 by Arabidopsis involves CERK1, LYK4 and LYK5, three of the eight members of the LysM PRR family. We found that aglucan-enriched wall fraction from the pathogenic fungus Plectosphaerella cucumerina which was devoid of GlcNAc activated immune responses in Arabidopsis wild-type plants but not in the cerk1 mutant. Using this differential response, we identified the non-branched 1,3-β-d-(Glc) hexasaccharide as a major fungal MAMP. Recognition of 1,3-β-d-(Glc)6 was impaired in cerk1 but not in mutants defective in either each of the LysM PRR family members or in the PRR-co-receptor BAK1. Transcriptomic analyses of Arabidopsis plants treated with 1,3-β-d-(Glc)6 further demonstrated that this fungal MAMP triggers the expression of immunity-associated genes. In silico docking analyses with molecular mechanics and solvation energy calculations corroborated that CERK1 can bind 1,3-β-d-(Glc)6 at effective concentrations similar to those of (GlcNAc)4 . These data support that plants, like animals, have selected as MAMPs the linear 1,3-β-d-glucans present in the walls of fungi and oomycetes. Our data also suggest that CERK1 functions as an immune co-receptor for linear 1,3-β-d-glucans in a similar way to its proposed function in the recognition of fungal chito-oligosaccharides and bacterial peptidoglycan MAMPs.

Absolute Configuration of Eight Cephalimysins Isolated from the Marine‐Derived Aspergillus fumigatus.

AbstractEight new metabolites with spiro‐heterocyclic γ‐lactam cores, cephalimysins E–L, were isolated from a culture broth of Aspergillus fumigatus that was originally separated from the marine fish Mugil cephalus. In spite of the presence of six chiral centers in cephalimysins E–L, no other diastereomers of them were isolated from the natural source except for eight unnatural forms that could be obtained by treating cephalimysins E–L with acidic methanol. The occurrence of cephalimysins E–L was rationalized via molecular energy calculations by assuming that these isomers were derived from annelation of a spiro‐heterocyclic γ‐lactam with an E‐olefin on the side chain such as the E‐isomer of pseurotin A. Biosynthetic consideration of the metabolites based on molecular orbital calculations demonstrated that the 16 stereoisomers can all exist, and their stereochemistry was unambiguously determined using circular dichroism spectra, nuclear Overhauser effect spectroscopy, and two‐dimensional nuclear magnetic resonance spectra.

Characterization of the ligand binding of PGRP-L in half-smooth tongue sole ( Cynoglossus semilaevis ) by molecular dynamics and free energy calculation

Background: Peptidoglycan (PGN) recognition proteins (PGRPs) are important pattern recognition receptors of the host innate immune system that are involved in the immune defense against bacterial pathogens. PGRPs have been characterized in several fish species. The PGN-binding ability is important for the function of PGRPs. However, the PGRP-PGN interaction mechanism in fish remains unclear. In the present study, the 3-D model of a long PGRP of half-smooth tongue sole (Cynoglossus semilaevis) (csPGRP-L), a marine teleost with great economic value, was constructed through the comparative modeling method, and the key amino acids involved in the interaction with Lys-type PGNs and Dap-type PGNs were analyzed by molecular dynamics and molecular docking methods. Results: csPGRP-L possessed a typical PGRP structure, consisting of five β-sheets and four α-helices. Molecular docking showed that the van der Waals forces had a slightly larger contribution than Coulombic interaction in the csPGRP-L-PGN complex. Moreover, the binding energies of csPGRP-L-PGNs computed by MM-PBSA method revealed that csPGRP-L might selectively bind both types of MTP-PGNs and MPP-PGNs. In addition, the binding energy of each residue of csPGRP-L was also calculated, revealing that the residues involved in the interaction with Lys-type PGNs were different from that with Dap-type PGNs. Conclusions: The 3-D structure of csPGRP-L possessed typical PGRP structure and might selectively bind both types of MTP- and MPP-PGNs, which provided useful insights to understanding the functions of fish PGRPs.

Where Is the Most Hydrophobic Region? Benzopurpurine Self-Assembly at the Calcite–Water Interface

Control of molecular self-assembly at solid–liquid interfaces is challenging due to the complex interplay between molecule–molecule, molecule–surface, molecule–solvent, surface–solvent, and solvent–solvent interactions. Here, we use in-situ dynamic atomic force microscopy to study the self-assembly of Benzopurpurine 4B into oblong islands with a highly ordered inner structure yet incommensurate with the underlying calcite (10.4) surface. Molecular dynamics and free energy calculations provide insights by showing that Benzopurpurine 4B molecules do not anchor to the surface directly but instead assemble on top of the second hydration layer. This seemingly peculiar behavior was then rationalized by considering that hydrophobic molecules placed atop the second water layer cause the least distortion to the existing hydration structure. Further experiments for the adsorption of Benzopurpurine 4B on other minerals indicate that the specific interfacial water structure on calcite is decisive for rationalizing th...

Restoring the Pauli principle in the random phase approximation ground state

Random phase approximation ground state contains electronic configurations where two (and more) identical electrons can occupy the same molecular spin-orbital violating the Pauli exclusion principle. This overcounting of electronic configurations happens due to quasiboson approximation in the treatment of electron-hole pair operators. We describe the method to restore the Pauli principle in the RPA wavefunction. The proposed theory is illustrated by the calculations of molecular dipole moments and electronic kinetic energies. The Hartree–Fock based RPA, which is corrected for the Pauli principle, gives the results of comparable accuracy with Møller-Plesset second order perturbation theory and coupled-cluster singles and doubles method.