Binding Energy Decomposition Research Articles

A comprehensive analysis of the spectroscopic and drug-like properties of dimethyl 5-hydroxybenzene-1,3-dicarboxylate: insights from DFT and MD simulations

ABSTRACT An in-depth investigation was undertaken to explore the ground-state molecular and electronic structure of Dimethyl 5-hydroxybenzene-1,3-dicarboxylate (D5HD). The potential energy scan of D5HD at various dihedral angles identified the lowest energy conformer, which was re-optimised at the higher basis set. The recorded FT-Raman and FT-IR spectra were compared with corresponding theoretical spectra, demonstrating a high degree of coherence. A comprehensive Natural Bond Orbital analysis was done for D5HD to gain insights for the overall electronic distribution within the molecule. Additionally, nonlinear optical (NLO) properties along with various DFT-based descriptors were calculated. Molecular docking studies against human acetylcholinesterase enzyme (PDB 2JF0), D5HD displayed good binding affinity. The study revealed that hydrogen bonded as well as van der Waals interactions exist between D5HD and different residues in the binding cavity of the target protein. The 100 ns MD simulation confirms the conformational stability of protein (2JF0)–ligand (D5HD) complex. The binding energy and residue decomposition analysis performed using MM-GBSA approach showed positive results with binding energy of −17.76 kcal/mol. Furthermore, D5HD effectively passed all pharmacokinetic filters, establishing its potential as a promising candidate in the quest for novel acetylcholinesterase inhibitors. Highlights Systematic exploration of the structure and spectroscopic properties of D5HD. Molecular docking between D5HD and acetylcholinesterase (PDB 2JF0) reveals the establishment of hydrogen bonds and Van der Waals interactions. D5HD successfully complies with all relevant pharmacokinetic filters. MD simulation analysis on 2JF0–D5HD complex confirms the conformational stability. Energy and residue decomposition based on MMGBSA approach.

Computational investigations of potential inhibitors of monkeypox virus envelope protein E8 through molecular docking and molecular dynamics simulations

The World Health Organization (WHO) has declared the monkeypox outbreak a public health emergency, as there is no specific therapeutics for monkeypox virus (MPXV) disease. This study focused on docking various commercial drugs and plant-derived compounds against the E8 envelope protein crucial for MPXV attachment and pathogenesis. The target protein structure was modeled based on the vaccinia virus D8L protein. Notably, maraviroc and punicalagin emerged as potential ligands, with punicalagin exhibiting higher binding affinity (− 9.1 kcal/mol) than maraviroc (− 7.8 kcal/mol). Validation through 100 ns molecular dynamics (MD) simulations demonstrated increased stability of the E8-punicalagin complex, with lower RMSD, RMSF, and Rg compared to maraviroc. Enhanced hydrogen bonding, lower solvent accessibility, and compact motions also attributed to higher binding affinity and stability of the complex. MM-PBSA calculations revealed van der Waals, electrostatic, and non-polar solvation as principal stabilizing energies. The binding energy decomposition per residue favored stable interactions between punicalagin and the protein’s active site residues (Arg20, Phe56, Glu228, Tyr232) compared to maraviroc. Overall study suggests that punicalagin can act as a potent inhibitor against MPXV. Further research and experimental investigations are warranted to validate its efficacy and safety.

Assessing the Efficacy of Acanthoic Acid Isolated from Acanthopanax koreanum Nakai in Male Infertility: An In Vivo and In Silico Approach.

Acanthoic acid, a diterpene isolated from the root bark of Acanthopanax koreanum Nakai, possesses diverse pharmacological activities, including anti-inflammatory, anti-diabetic, gastrointestinal protection, and cardiovascular protection. This study is the first to investigate the egg-hatching rates of Drosophila melanogaster affected by acanthoic acid. Notably, male flies supplemented with 10 μM acanthoic acid exhibited a strong increase in hatching rates compared with controls under adverse temperature conditions, suggesting a potential protective effect against environmental stressors. Molecular docking simulations revealed the binding affinities and specific interactions between acanthoic acid and proteins related to male infertility, including SHBG, ADAM17, and DNase I, with binding affinity values of -10.2, -6.8, and -5.8 kcal/mol, respectively. Following the docking studies, molecular dynamic simulations were conducted for a duration of 100 ns to examine the stability of these interactions. Additionally, a total binding energy analysis and decomposition analysis offered insights into the underlying energetic components and identified key contributing residues.

Binding selectivity analysis of new delhi metallo-beta-lactamase-1 inhibitors using molecular dynamics simulations: Exploring possibilities for decoding antimicrobial drug resistance

BackgroundNew Delhi metallo-beta-lactamase-1 (NDM1) confers resistance to several bacterial species against a broad range of beta-lactam antibiotics and turning them into superbugs that pose a significant threat to healthcare systems worldwide. As such, it is a potentially relevant biological target for counteracting bacterial infections. Given the lack of effective treatment options against NDM1 producing bacteria, finding a reliable inhibitor for the NDM1 enzyme is crucial. MethodsUsing molecular dynamics simulations, the binding selectivities and affinities of three ligands, viz. PNK, 3S0, and N1G were investigated against NDM1. ResultsThe results indicate that N1G binds with more affinity to NDM1 than PNK and 3S0. The binding energy decomposition analysis revealed that residues I35, W93, H189, K211, and N220 showed significant binding energies with PNK, 3S0, and N1G, and hence are crucially involved in the binding of the ligands to NDM1. Molecular dynamics trajectory analysis further elicited that the ligands influence dynamic flexibility of NDM1 morphology, which contributes to the partial selectivities of PNK, 3S0, and N1G. ConclusionsThis in silico study offers a vital information for developing potential NDM1 inhibitors with high selectivity. Nevertheless, in vitro and in vivo experimental validation is mandated to extend the possible applications of these ligands as NDM1 inhibitors that succor in combating antimicrobial resistance.

Binding selectivity analysis of AURKs inhibitors through molecular dynamics simulation studies.

Aurora kinases (AURKs) have been identified as promising biological targets for the treatment of cancer. In this study, molecular dynamics simulations were employed to investigate the binding selectivity of three inhibitors (HPM, MPY, and VX6) towards AURKA and AURKB by predicting their binding free energies. The results show that the inhibitors HPM, MPY, and VX6 have more favorable interactions with AURKB as compared to AURKA. The binding energy decomposition analysis revealed that four common residue pairs (L139, L83), (V147, V91), (L210, L154), and (L263, L207) showed significant binding energies with HPM, MPY, and VX6, hence responsible for the binding selectivity of AURKA and AURKB to the inhibitors. The MD trajectory analysis also revealed that the inhibitors affect the dynamic flexibility of protein structure, which is also responsible for the partial selectivity of HPM, MPY, and VX6 towards AURKA and AURKB. As expected, this study provides useful insights for the design of potential inhibitors with high selectivity for AURKA and AURKB.

A Free Energy Decomposition Analysis: Insight into Binding Thermodynamics from Absolutely Localized Molecular Orbitals.

Traditional energy decomposition analysis (EDA) methods can provide an interpretive decomposition of non-covalent electronic binding energies. However, by definition, they neglect entropic effects and nuclear contributions to the enthalpy. With the objective of revealing the chemical origins of trends in free energies of binding, we introduce the concept of a Gibbs decomposition analysis (GDA) by coupling the absolutely localized molecular orbital treatment of electrons in non-covalent interactions with the simplest possible quantum rigid rotor-harmonic oscillator treatment of nuclear motion at finite temperature. The resulting pilot GDA is employed to decompose enthalpic and entropic contributions to the free energy of association of the water dimer, fluoride-water dimer, and water binding to an open metal site in the metal-organic framework Cu(I)-MFU-4l. The results show enthalpic trends that generally track the electronic binding energy and entropic trends that reveal the increasing price of loss of translational and rotational degrees freedom with temperature.

In silico pharmacokinetics, molecular docking and dynamic simulation studies of endolichenic fungi secondary metabolites: An implication in identifying novel kinase inhibitors as potential anticancer agents

Herein, seventy three (73) anticancer metabolites from different endolichenic fungi which are reported previously, were analyzed for drug likeliness and pharmacokinetic properties using SwissADME, ADMETlab, and admetSAR. The desirable compounds were studied using molecular docking against three clinically important human kinases: pyruvate kinase isoform 2, hexokinase II, and phosphoglycerate kinase. The results displayed a significant binding affinity of the test ligands against the kinases compared to 3-bromopyruvic acid, a reference glycolytic inhibitor. Pharmacokinetics and binding interactions of three compounds including talaromycin A, pyridoxatin, and terricollene A were predicted to be substantial. Terricollene A bound complexes were found to have the most considerable binding free energies and therefore were investigated for their conformational stability and compactness under explicit water conditions using molecular dynamics simulation up to 100 ns. The residual decomposition of binding energies for each of the complexes was calculated using Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) method. The results demonstrated substantial stability and compactness of terricollene A-kinase complexes. The findings will facilitate the development of potential glycolytic inhibitors for treating and controlling several forms of cancer; however, supplementary experimental investigations to evaluate the efficacy of the test ligand are warranted.

Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects.

A nicotinamide-based derivative was designed as an antiproliferative VEGFR-2 inhibitor with the key pharmacophoric features needed to interact with the VEGFR-2 catalytic pocket. The ability of the designed congener ((E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound 10, to bind with the VEGFR-2 enzyme was demonstrated by molecular docking studies. Furthermore, six various MD simulations studies established the excellent binding of compound 10 with VEGFR-2 over 100 ns, exhibiting optimum dynamics. MM-GBSA confirmed the proper binding with a total exact binding energy of −38.36 Kcal/Mol. MM-GBSA studies also revealed the crucial amino acids in the binding through the free binding energy decomposition and declared the interactions variation of compound 10 inside VEGFR-2 via the Protein–Ligand Interaction Profiler (PLIP). Being new, its molecular structure was optimized by DFT. The DFT studies also confirmed the binding mode of compound 10 with the VEGFR-2. ADMET (in silico) profiling indicated the examined compound’s acceptable range of drug-likeness. The designed compound was synthesized through the condensation of N-(4-(hydrazinecarbonyl)phenyl)benzamide with N-(4-acetylphenyl)nicotinamide, where the carbonyl group has been replaced by an imine group. The in-vitro studies were consonant with the obtained in silico results as compound 10 prohibited VEGFR-2 with an IC50 value of 51 nM. Compound 10 also showed antiproliferative effects against MCF-7 and HCT 116 cancer cell lines with IC50 values of 8.25 and 6.48 μM, revealing magnificent selectivity indexes of 12.89 and 16.41, respectively.

The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches

Corresponding to the reported features of anti-VEGFR-2-approved compounds, a new 1H-indole derivative (compound 7) was designed. The inhibitory potential of the designed compound was revealed via a molecular docking study that showed the appropriate binding. Then, MD simulation (six studies) over a period of 100 ns was performed to confirm the precise binding and optimum energy. Additionally, MM-GBSA reaffirmed the perfect binding, exhibiting a total precise energy of −40.38 Kcal/Mol. The MM-GBSA experiments named the essential amino acids in the protein–ligand interaction, employing the binding energy decomposition and revealing the diversity of interactions of compound 7 inside the VEGFR-2 enzyme. As compound 7 is new, DFT experiments were utilized for molecular structure optimization. Additionally, the DFT results validated the coherent interaction of compound 7 with the VEGFR-2 enzyme. A good value of drug-likeness of compound 7 was acknowledged via in silico ADMET studies. Interestingly, the experimental in vitro prohibitory potential of compound 7 was better than that of sorafenib, demonstrating an IC50 value of 25 nM. Notably, the strong inhibitory effects of compound 10 against two cancer cell lines (MCF-7 and HCT 116) were established with IC50 values of 12.93 and 11.52 μM, disclosing high selectivity indexes of 6.7 and 7.5, respectively.

Screening of potent STAT3-SH2 domain inhibitors from JAK/STAT compound library through molecular dynamics simulation.

The Signal Transducer and Activator of Transcription 3 (STAT3) protein is activated consistently in the tumor cells and thus studied as a potent target for cancer prevention. The TYR705-phosphorylated (pTyr) STAT3 forms a homo-dimer by binding to its recognition site in the Src Homology 2 (SH2) domain of another STAT3 monomer, causing cellular survival, proliferation, inflammation, and tumor invasion. Many inhibitors of STAT3-SH2 have recently been identified using both computational and experimental approaches. In this study, we used molecular docking, Absorption, Distribution, Metabolism, and Excretion/Toxicological (ADME/tox) and molecular dynamics modeling to examine binding affinities and specificities of 191 inhibitor drugs from the SELLECKCHEM database. The binding free energies of the inhibitors were calculated by Induced Fit Docking (IFD) prime energy. The binding hotspots of STAT3-SH2 were evaluated via binding energy decomposition and hydrogen bond distribution analysis, and the inhibitor compound's stability was assessed through MD simulation. (-)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, Picroside I, Saikosaponin D, and Ginsenoside Rk1 were found to be the top hit inhibitor compounds. They exhibited an exceptional docking score, a low binding free energy, interacted with the key amino acid residue, and showed significant ADME/tox moderation. These compounds were further proved to be favorable by their stability in an MD simulation run for 100ns using GROMACS software. The inhibitors (-)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, and Saikosaponin D show improved stability in molecular dynamic modeling and are expected to have a significant STAT3-SH2 inhibitory effect against cancer.

The Role of Packing, Dispersion, Electrostatics, and Solvation in High-Affinity Complexes of Cucurbit[n]urils with Uncharged Polar Guests.

The rationalization of non‐covalent binding trends is both of fundamental interest and provides new design concepts for biomimetic molecular systems. Cucurbit[n]urils (CBn) are known for a long time as the strongest synthetic binders for a wide range of (bio)organic compounds in water. However, their host‐guest binding mechanism remains ambiguous despite their symmetric and simple macrocyclic structure and the wealth of literature reports. We herein report experimental thermodynamic binding parameters (ΔG, ΔH, TΔS) for CB7 and CB8 with a set of hydroxylated adamantanes, di‐, and triamantanes as uncharged, rigid, and spherical/ellipsoidal guests. Binding geometries and binding energy decomposition were obtained from high‐level theory computations. This study reveals that neither London dispersion interactions, nor electronic energies or entropic factors are decisive, selectivity‐controlling factors for CBn complexes. In contrast, peculiar host‐related solvation effects were identified as the major factor for rationalizing the unique behavior and record‐affinity characteristics of cucurbit[n]urils.

Pharmacophore-Based Virtual Screening and Molecular Dynamics Simulation for Identification of a Novel DNA Gyrase B Inhibitor with Benzoxazine Acetamide Scaffold.

DNA gyrase B is one of the enzyme targets for antimicrobial drug development, and its absence in mammals makes it a suitable target for the creation of safe antibacterial drugs. We identified six novel hits as DNA gyrase B inhibitors in the present study by employing 3D-pharmacophore structure-based virtual screening. The lead compounds complied with drug-likeness rules and lacked toxicity. Compound 4 (ZINC32858011) showed the highest inhibitory activity with an IC50 value of 6.3 ± 0.1 μM against the DNA gyrase enzyme. In contrast, the positive controls ciprofloxacin and novobiocin used in enzyme inhibition assay had IC50 values of 14.4 ± 0.2 and 12.4 ± 0.2 μM, respectively. The molecular docking of the six hits demonstrated that compounds 1, 2, 4, and 6 had suitable fitting modes inside the binding pocket. Molecular dynamics simulations were carried out for the six hits and the rmsd, rmsf, radius of gyration, and solvent accessible surface area parameters obtained from 100 ns molecular dynamics simulations for the six compounds complexed with a DNA gyrase B protein indicated that compound 4 (ZINC32858011) formed the most stable complex with DNA gyrase B. The binding free energy calculation with the MM-PBSA method suggested that the van der Waals interaction, followed by electrostatic force, played a significant role in the binding. Per-residue free binding energy decomposition showed that Ile78 contributed the most for the binding energy followed by Asn46, Asp49, Glu50, Asp73, Ile78, Pro79, Ala86, Ile90, Val120, Thr165, and Val167.

Computational Interaction Analysis of Sirex noctilio Odorant-Binding Protein (SnocOBP7) Combined with Female Sex Pheromones and Symbiotic Fungal Volatiles

Sirex noctilio, a major forestry quarantine pest, has spread rapidly and caused serious harm. However, existing methods still need to be improved because its olfactory interaction mechanisms are poorly understood. In order to study the role of male-specific protein SnocOBP7 in the protein–ligand interactions, we selected it as the object of computational simulation and analysis. By docking it with 11 ligands and evaluating free binding energy decomposition, the three best binding ligands were found to be female sex pheromones ((Z)-7-heptacosene and (Z)-7-nonacosene) and symbiotic fungal volatiles ((−)-globulol). Binding mode analysis and computational alanine scanning suggested that five residues play key roles in the binding of each female sex pheromone to SnocOBP7, whereas two residues play key roles in (−)-globulol binding. Phe108 and Leu36 may be the crucial sites via which SnocOBP7 binds female sex pheromones, whereas Met40 may regulate the courtship behavior of males, and Leu61 may be related to mating and host finding. Our studies predicted the function of SnocOBP7 and found that the interaction between SnocOBP7 and pheromone is a complex process, and we successfully predicted its binding key amino-acid sites, providing a basis for the development of new prevention and control methods relying on female sex pheromones and symbiotic fungi.

Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach

Aurora kinase B plays an important role in the cell cycle to orchestrate the mitotic process. The amplification and overexpression of this kinase have been implicated in several human malignancies. Therefore, Aurora kinase B is a potential drug target for anticancer therapies. Here, we combine atom-based 3D-QSAR analysis and pharmacophore model generation to identify the principal structural features of acylureidoindolin derivatives that could potentially be responsible for the inhibition of Aurora kinase B. The selected CoMFA and CoMSIA model showed significant results with cross-validation values (q2) of 0.68, 0.641 and linear regression values (r2) of 0.971, 0.933 respectively. These values support the statistical reliability of our model. A pharmacophore model was also generated, incorporating features of reported crystal complex structures of Aurora kinase B. The pharmacophore model was used to screen commercial databases to retrieve potential lead candidates. The resulting hits were analyzed at each stage for diversity based on the pharmacophore model, followed by molecular docking and filtering based on their interaction with active site residues and 3D-QSAR predictions. Subsequently, MD simulations and binding free energy calculations were performed to test the predictions and to characterize interactions at the molecular level. The results suggested that the identified compounds retained the interactions with binding residues. Binding energy decomposition identified residues Glu155, Trp156 and Ala157 of site B and Leu83 and Leu207 of site C as major contributors to binding affinity, complementary to 3D-QSAR results. To best of our knowledge, this is the first comparison of WaterSwap field and 3D-QSAR maps. Overall, this integrated strategy provides a basis for the development of new and potential AK-B inhibitors and is applicable to other protein targets.

Intermolecular driving forces on the adsorption of DNA/RNA nucleobases to graphene and phosphorene: An atomistic perspective from DFT calculations

Graphene and phosphorene show a strong affinity towards DNA/RNA nucleobases, serving as promising materials to be integrated as part of bioinorganic interfaces for either self-assembly, sensing, or sequencing of DNA/RNA constituents. Here, the intermolecular driving forces determining the adsorption of DNA/RNA nucleobases and base-pairs onto graphene and phosphorene are studied with density functional theory (DFT) calculations in the gas phase and solution with a polarizable continuum model (PCM). The formed complexes are studied through binding analyses (adsorption energy, AIM, IGM), charge transfer, and energy decomposition analyses based on absolutely localized molecular orbitals (ALMO-EDA). It is found that nucleobases are adsorbed with similar stability onto graphene and phosphorene in stacked patterns. Electrostatics and dispersion effects are the primary stabilizing intermolecular forces, standing for ~85% of the stabilizing energy. Dispersion is higher than electrostatic effects for nucleobase-Graphene complexes; conversely, nucleobase-Phosphorene complexes show a greater contribution from electrostatics to the stability. Moreover, solvent effects lead to energy destabilization of complexes with respect to the gas phase due to the relative difference in the solute-solvent polarity of the components, which are higher for those complexes stabilized by electrostatic forces. Consequently, the adsorption on phosphorene is more destabilized than graphene in aqueous solution; while, dispersion/electrostatic effects turn almost balanced for nucleobase-Phosphorene complexes in solution as a result of the decrease in the magnitude of electrostatic interactions. Otherwise, an extra energy lowering is reached by adsorption with phosphorene due to the high adsorbent polarizability and its response upon nucleobase adsorption; nevertheless, Pauli repulsion compensates all the stabilizing effects due to the larger electron density of the phosphorene surface compared to graphene. Finally, physical effects along the dissociation path reveal the dominant factors on the stabilization of the nucleobase-Graphene(Phosphorene) complexes during the entire adsorption process.

Molecular dynamics simulation, free energy landscape and binding free energy computations in exploration the anti-invasive activity of amygdalin against metastasis

Background and objectiveHistorically, amygdalin has been used as alternative medicine or in vitro and in vivo studies, but no single study exists which discusses the structural mechanism of amygdalin at a molecular level. This paper inquiries into the inhibitory actions of amygdalin on the selected targets: AKT1, FAK, and ILK, which are regulators for various mediated signaling pathways, and are associated with cell adhesion, migration, and differentiation. In order to get details at the molecular level of amygdalin's inhibitory activities against chosen proteins, molecular modeling and simulation techniques including double docking, molecular dynamics simulation, free energy landscape analysis, and binding free energy calculation were exerted. MethodsTo get molecular level details of amygdalin inhibitory effects against the relevant proteins; here the utilized tools are the following: the double docking, molecular dynamics simulation, free energy landscape analysis, g_mmpbsa, and interaction entropy were used to evaluate the inhibitory activity against targeted proteins. ResultsThe computational calculations revealed that amygdalin inhibits the selected targets via block the ATP-binding pocket of AKT1, FAK, and ILK by forming stable hydrogen bonds. Moreover, free energy landscape, FEL exposed that amygdalin stabilized the global conformations of both FAK and ILK proteins to the minimum global energy besides it reduced the essential dynamics of FAK and ILK proteins. MMPBSA computations provided further evidence for amygdalin's stability inside the ATP-binding pocket of AKT1, FAK, and ILK with a binding free energy of 45.067, −13.033, 13.109 kJ/mol, respectively. The binding free energies are lastly consistent with the hydrogen bonding and pairs within 0.35 nm results. The decomposition of binding energy shows the pivotal amino acid residues responsible for the stability of amygdalin's interactions inside the ATP-binding sites by forming hydrogen bonds. ConclusionsBefore this work, it was enigmatic to make predictions about how amygdalin inhibits metastasis of cancer. But the computational results contribute in several ways to our understanding of amygdalin activity and provide a basic insight into the activity of amygdalin as a multi-target drug in the metastasis and invasion of cancer.

Sulfur hydrogen bonding and internal dynamics in the monohydrates of thenyl mercaptan and thenyl alcohol.

The monohydrates of thenyl alcohol and thenyl mercaptan have been probed in a supersonic jet expansion using chirped-pulse and Fabry-Perot Fourier-transform microwave spectroscopy. The rotational spectra revealed a single isomer for each of the dimers. The thenyl alcohol hydrate is stabilized by an O-HOw hydrogen bond between the alcohol and water, with water acting as a proton acceptor and additionally engaging in an Ow-Hπ interaction with the thenyl ring. Conversely, water behaves as a proton donor in the thenyl mercaptan hydrate, linking to the thiol group though an Ow-HS hydrogen bond and secondary Ow-Hπ interactions with the ring. In both dimers water retains internal mobility, as tunneling doublings in the spectrum confirm an internal rotation motion of water inside the cluster. The experimental results have been complemented with density-functional-theory molecular orbital calculations, binding energy decomposition and a topological analysis of the electronic density, providing a comparative description of the effects of hydrogen bonding of water to the alcohol and thiol groups in the dimers, relevant to understand hydrogen bonding to sulfur centers.

Dimerization energetics of the G-protein coupled bile acid receptor TGR5 from all-atom simulations.

We describe the first extensive energetic evaluation of GPCR dimerization on the atomistic level by means of potential of mean force (PMF) computations and implicit solvent/implicit membrane end-point free energy calculations (MM-PBSA approach). Free energies of association computed from the PMFs show that the formation of both the 1/8 and 4/5 interface is energetically favorable for TGR5, the first GPCR known to be activated by hydrophobic bile acids and neurosteroids. Furthermore, formation of the 1/8 interface is favored over that of the 4/5 interface. Both results are in line with our previous FRET experiments in live cells. Differences in lipid-protein interactions are identified to contribute to the observed differences in free energies of association. A per-residue decomposition of the MM-PBSA effective binding energy reveals hot spot residues specific for both interfaces that form clusters. This knowledge may be used to guide the design of dimerization inhibitors or perform mutational studies to explore physiological consequences of distorted TGR5 association. Finally, we characterized the role of Y111, located in the conserved (D/E)RY motif, as a facilitator of TGR5 interactions. The types of computations performed here should be transferable to other transmembrane proteins that form dimers or higher oligomers as long as good structural models of the dimeric or oligomeric states are available. Such computations may help to overcome current restrictions due to an imperfect energetic representation of protein association at the coarse-grained level. © 2019 Wiley Periodicals, Inc.

Theoretical study on the weak interaction and energy performance of nitroformate salts and nitroformate-based propellant formulations.

Nitroformate energetic salts are potential high-performance oxidizers which can be used in a solid propellant. The geometric configuration, the weak interaction, and the energy characteristics of hydrazine nitroformate (HNF), ammonium nitroformate (ANF), aminotriazole nitroformate (ATNF), guanidinium nitroformate (GNF), and aminotetrazole nitroformate (ATTNF) were investigated. Analysis results show that there exist hydrogen bonds in all salts except GNF. The binding energies of salt are between 390 and 430kJ/mol and are positively correlated with densities and thermodynamic stabilities of salts but show reverse trend on impact sensitivities. Binding energy decomposition indicates that the main interaction in anion and cation is electrostatic interaction. The detonation velocity and specific impulse of five nitroformate salts are in the range of 8.6~9.1km/s and 2200~2600Ns/kg, respectively. Considering the five selected salts as oxidizers, several propellant formulations were designed and the performances of formulations were predicted. The calculation results show that nitroformate salts obviously reduce characteristic signals and improve specific impulse for propellant formulations.

Recognition of a Key Anchor Residue by a Conserved Hydrophobic Pocket Ensures Subunit Interface Integrity in DNA Clamps

Sliding clamp proteins encircle duplex DNA and are involved in processive DNA replication and the DNA damage response. Clamp proteins are ring-shaped oligomers (dimers or trimers) and are loaded onto DNA by an ATP-dependent clamp loader complex that ruptures the interface between two adjacent subunits. Here we measured the solution dynamics of the human clamp protein, proliferating cell nuclear antigen, by monitoring the change in the fluorescence of a site-specifically labeled. To unravel the origins of clamp subunit interface stability, we carried out comprehensive comparative analysis of the interfaces of seven sliding clamps. We used computational modeling (molecular dynamic simulations and MM/GBSA binding energy decomposition analyses) to identify conserved networks of hydrophobic residues critical for clamp stability and ring-opening dynamics. The hydrophobic network is shared among clamp proteins and exhibits a “key in a keyhole” pattern where a bulky aromatic residue from one clamp subunit is anchored into a hydrophobic pocket of the opposing subunit. Bioinformatics and dynamic network analyses showed that this oligomeric latch is conserved across DNA sliding clamps from all domains of life and dictates the dynamics of clamp opening and closing.