Quantum mechanical/molecular mechanical (QM/MM) and quantum mechanical charge field (QMCF) molecular (MD) simulations have been performed to describe structural and dynamical properties of Na(I) and ...K(I) in water and to compare the two approaches. The first and second hydration shells were treated by ab initio quantum mechanics at the restricted Hartree−Fock (RHF) level. The structural data are in good agreement with previously published experimental and theoretical results. A considerable number of water exchange reactions were observed within the first shell during the simulation time of 12 ps. The number of exchange events in both shells is higher in the case of K(I) than Na(I) reflecting the weaker ion−ligand bond strength of K(I). Comparison of the “conventional” QM/MM framework with the QMCF method clearly indicates the latter to be advantageous, as ambiguities arising from the coupling of the subregions occurring in the QM/MM MD simulations did not evolve when the QMCF ansatz was applied.
Human paraoxonase 1 (huPON1) is a calcium-dependent esterase responsible for hydrolysis of a wide variety of substrates including organophosphates, esters, lactones, and paraoxon. Although its ...natural substrate is unknown, the action of PON as an antioxidant is well documented. Because recent reports have suggested glycation may induce reduced PON activity in diabetes, we investigated the structural features of huPON1 and its glycated mutant by template-based modeling, docking, and molecular dynamics (MD) simulations. Our results corroborated the importance of the His115–His134 dyad in both the lactonase and paraoxonase activity of huPON1. Structural alterations in the glycated model reflected weak interactions between the docked substrate and the active site cleft. We also used MD simulation to gain insight into glycation-induced conformational changes of huPON1 and the implication of this on depleted enzymatic activity. The catalytic calcium found on the surface interacts with the side chain oxygen of residues, including Asn224, Asn270, Asn168, Asp269, and Glu53, and this interaction with the respective residues undergoes minor displacement on glycation. The root-mean-square fluctuation had high motional flexibility in the non-glycated model whereas the conformation of the glycated structure was comparatively stable. Our findings emphasize the consequence of glycation-induced alterations and their effect on overall enzymatic activity.
A quantum mechanical charge field (QMCF) molecular dynamics (MD) simulation including the first and second hydration shells in the QM region has been carried out to describe the structural and ...dynamical properties of Be2+ in aqueous solution. In this methodology, the full first and second hydration shells are treated by ab initio quantum mechanics supplemented by a fluctuating electrostatic embedding technique. From the simulation, structural properties were extracted and were found to be in good agreement with previously published experimental and theoretical results. The radial distribution function (RDF) showed the maximum probability of the Be−O bond length at 1.62 Å. The first tetrahedrally arranged hydration shell is highly inert with respect to ligand-exchange processes. Application of local-density-corrected three-body correlation analysis showed minor structural influence of the ion beyond the second hydration layer, contrary to the findings of a previous QM/MM MD simulation. The dynamics of the hydrate were studied in terms of ligand mean residence times (MRTs) and the power spectrum of the Be2+−O stretching frequency. A comparison of the “classical” QM/MM framework with the QMCF method clearly demonstrated the advantages of the latter, as ambiguities arising from the coupling of the subregions occurring in QM/MM MD simulations did not appear when the QMCF ansatz was applied.
The optimized energy and geometry for Na
+– and K
+–water complexes in gaseous phase have been studied using different methods such as HF, MP2, B3LYP, and CCSD. Classical and quantum ...mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations have been performed to describe structural and dynamical properties of Na
+ and K
+ in water and to compare the two approaches. The first hydration shell was treated by
ab initio quantum mechanics at restricted Hartree–Fock (RHF) level using the Los Alamos LANL2DZ ECP basis set for the cations Na
+ and K
+ and Dunning double-
ζ plus polarisation basis set for O and H. The results obtained are in good agreement with previously published experimental and theoretical results. In the QM/MM method, the radial distribution function (RDF) showed the maximum probability of the Na–O and K–O bond lengths at 2.39
Å and 2.85
Å, respectively. A considerable number of water exchange reactions were observed within the first shell during the simulation time of 16 and 12
ps of Na
+ and K
+ ions in aqueous solution, respectively. The number of exchange events in both first and second shells is higher in the case of K
+ than Na
+ indicating the weaker ion-ligand strength of K
+.
A quantum mechanical charge field molecular dynamics simulation of Ge(II) in aqueous solution revealed a distorted hydration with two tri-pyramidal substructures.
Quantum mechanical charge field ...(QMCF) molecular dynamics (MD) simulations including first and second hydration shell in the QM region have been performed to describe structural and dynamical properties of Ge(II) in water. The first and second hydration shells were treated by
ab initio quantum mechanics at restricted Hartree-Fock (RHF) level. The radial distribution function (RDF) showed the maximum probability of the Ge–O bond length at 2.04
Å, accompanied by an extended first shell located at ∼2.8
Å. A uniquely distorted hydration structure with two tri-pyramidal substructures provides a new basis for the interpretation of the kinetic properties of germanium(II) complexes.
Structural and dynamical properties of Ge (II) in aqueous solution have been investigated using the novel ab initio quantum mechanical charge field (QMCF) molecular dynamics (MD) formalism. The first ...and second hydration shells were treated by ab initio quantum mechanics at restricted Hartree-Fock (RHF) level using the cc-pVDZ-PP basis set for Ge (II) and Dunning double-ζ plus polarization basis sets for O and H. Besides ligand exchange processes and mean ligand residence times to observe dynamics, tilt- and theta-angle distributions along with an advanced structural parameter, namely radial and angular distribution functions (RAD) for different regions were also evaluated. The combined radial and angular distribution depicted through surface plot and contour map is presented to provide a detailed insight into the density distribution of water molecules around the Ge²⁺ ion. A strongly distorted hydration structure with two trigonal pyramidal substructures within the first hydration shell is observed, which demonstrates the lone-pair influence and provides a new basis for the interpretation of the catalytic and pharmacological properties of germanium coordination compounds.
Proteins have a vital role in the structure and function of biological entities. Enzymes are responsible for catalyzing many biochemical processes and at the same time enzyme inhibition studies have ...drawn attention for remedial purposes. The technique of molecular docking is employed to predict the structure of the intermolecular complex formed between the enzyme and its inhibitor. Alpha-glucosidase is a calcium containing enzyme. The inhibition of alpha-glucosidase enzyme is crucial for glycemic control. This is connected with AIDS treatment as it is recently reported that the viral glycoprotein synthesis depends upon the activity of the enzyme. The structural and functional details of alpha glucosidase enzyme have been studied using molecular dynamics simulation. Root mean square deviation (RMSD) values were calculated relative to the starting structure at 300K and at time t=0. Root mean square fluctuation (RMSF) values were calculated relative to the average structure obtained from the 300K simulation. The production run was performed at 300K under periodic boundary conditions for 5ns. Both root mean square deviation and fluctuation analyses indicated the presence of disorderedness of atoms along the glucosidase polypeptide chain.
► Energy minimization ► Structure validation ► Molecular dynamics simulation ► Investigation of dynamic properties of enzyme with its inhibitor ► Connection of function and structural variability of the system
Databases are integral part of bioinformatics and need to be accessed most frequently, thus downloading and updating them on a regular basis is very critical. The establishment of bioinformatics ...research facility is a challenge for developing countries as they suffer from inherent low-bandwidth and unreliable internet connections. Therefore, the identification of techniques supporting download and automatic synchronization of large biological database at low bandwidth is of utmost importance. In current study, two protocols (FTP and Bit Torrent) were evaluated and the utility of a BitTorren based peer-to-peer (btP2P) file distribution model for automatic synchronization and distribution of large dataset at our facility in Pakistan have been discussed.
•· Eight new bioactive bismuth(III) hydrazones were synthesized and fully characterized, besides the solvent molecule, DMSO, contribute to their structural motifs.•X-ray structure for 1revealed ...a distinctive seven coordinated Bi(III) center, assuming pentagonal bipyramidal molecular geometry.•· The compounds 6, 7and8exhibited significant antidiabetic activity.•· Molecular docking study revealed significant activity of 2 against Human pancreatic alpha amylase with the highest GOLD fitness score.•· The docking data for (1) described its active role against H. pylori urease having the highest GOLD fitness score.
Eight new bismuth(III) complexes (1-8) of substituted hydrazones having general formula; Bi(RCONHNCHC5H4N)Clx and Bi(RCONHNCHC9H6N)Clx, where R = C10H7O (1, and 8), C4H3S (2), C6H5O (3, and 6), C7H7(4), C5H4N (5, and 7), x = 2 or 3 have been prepared. The substituted hydrazones (I1-I8) were synthesized by reacting the stoichiometric amounts of the respective hydrazides such as p-toluic hydrazide, 4-hydroxybenzhydrazide, thiophene-2-carboxylic acid hydrazide, 3-hydroxy-2-naphthoic acid hydrazide, Isonicotic acid hydrazide and appropriate aromatic aldehydes like pridine-2-carboxaldehyde and quinoline-2-carboxyaldehyde. These hydrazones (ligands),then complexed to Bi(III) species to yield the target compounds. They were characterized by FTIR, and NMR spectroscopy to find out an explicit evidence about their structural motifs. The X-ray data for (1 & I6) further validate the chemical structures of the synthesized compounds. The molecular geometry for (1) is predominately distorted pentagonal bipyramidal where hepta-coordinated Bi(III) center is attached to the nitrogens of pyridine and of azomethine moieties along with the carbonyl oxygen, two chloro and two oxygens of the (two) DMSO molecules. The bond lengths for Bi(1)-O(1), Bi(1)-N(1) and Bi(1)-N(2) are 2.323(5), 2.539(6), 2.390(5) oA respectively indicating Bi(1)-O(1) as the strongest linkage to the metal center. The H-bonding, present in (1), contributed an extra stability to the structure. The synthesized compounds were initially screened for their possible antimicrobial, alpha-amylase, and protein kinase inhibition, some (1,2,6,8) exhibit significant activity. The experimental results are further endorsed by molecular docking studies against helicobacter pylori urease (1E9Y), epidermal growth factor receptor tyrosine kinase (1M17) and human pancreatic alpha amylase (5U3A) inhibition activity. The significant ligand-receptor interactions, observed at the binding pocket of the selected drug targets, further revealed the enzyme inhibition potential of the compounds and highlighting their possible roles as therapeutic agents in future drug discovery processes.
Wnt-4 is an important signaling protein of the Wnt family that acts in paracrine manner to a few cell diameters. Wnt-4 takes part in many developmental processes including sex determination, and ...kidney development and also plays role in brain as well. Wnt-4 has a total of 25 cysteine residues with conserved locations in relation to whole Wnt family. Due to unchallenged importance of Wnts and to study their unusual fold, Wnt-4 was considered for simulation to interpret and extract structural features dynamically. Comparative modeling approach was utilized to model Wnt-4 and minimized to remove any energy restraints. The minimized model was then subjected to molecular dynamics simulation with periodic boundary conditions, to understand its behavior in the presence of water-box. Wnt-4 behavior for 20-nanosecond (ns) simulation was analyzed by calculating the root mean square deviation (RMSD), root mean square fluctuation (RMSF), and b-factor. Prominently, twenty (20) cysteine residues were observed in the edges of loops participating in interactions with frizzled receptors. The higher values of RMSD with comparison to higher values of RMSF and b-factor of residues accompanying 20 cysteine residues lying in regions nearer to N- and C-terminal domains extrapolate that these residues might be involved in cysteine–cysteine disulfide linkages and are more important structurally and functionally as well.
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•Energy minimization•Structure validation•Molecular dynamics simulation•Connection of function and structural variability of the Wnt-4•Importance of thumb-index fold
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