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Fulltext In Silico Screening of Aptamers Configuration against Hepatitis B Surface Antigen

Sabri MZ, Abdul Hamid AA, Sayed Hitam SM, Abdul Rahim MZ

Adv Bioinformatics, 2019;2019:6912914.
PMID: 31346332 DOI: 10.1155/2019/6912914

Aptamer has been long studied as a substitute of antibodies for many purposes. However, due to the exceeded length of the aptamers obtained in vitro, difficulties arise in its manipulation during its molecular conjugation on the matrix surfaces. Current study focuses on computational improvement for aptamers screening of hepatitis B surface antigen (HBsAg) through optimization of the length sequences obtained from SELEX. Three original aptamers with affinity against HBsAg were truncated into five short hairpin structured aptamers and their affinity against HBsAg was thoroughly studied by molecular docking, molecular dynamics (MD) simulation, and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method. The result shows that truncated aptamers binding on HBsAg "a" determinant region are stabilized by the dynamic H-bond formation between the active binding residues and nucleotides. Amino acids residues with the highest hydrogen bonds hydrogen bond interactions with all five aptamers were determined as the active binding residues and further characterized. The computational prediction of complexes binding will include validations through experimental assays in future studies. Current study will improve the current in vitro aptamers by minimizing the aptamer length for its easy manipulation.

Matched MeSH terms: Molecular Dynamics Simulation
Fulltext Nano-Level Damage Characterization of Graphene/Polymer Cohesive Interface under Tensile Separation

Koloor SSR, Rahimian-Koloor SM, Karimzadeh A, Hamdi M, Petrů M, Tamin MN

Polymers (Basel), 2019 Sep 02;11(9).
PMID: 31480660 DOI: 10.3390/polym11091435

The mechanical behavior of graphene/polymer interfaces in the graphene-reinforced epoxy nanocomposite is one of the factors that dictates the deformation and damage response of the nanocomposites. In this study, hybrid molecular dynamic (MD) and finite element (FE) simulations of a graphene/polymer nanocomposite are developed to characterize the elastic-damage behavior of graphene/polymer interfaces under a tensile separation condition. The MD results show that the graphene/epoxy interface behaves in the form of elastic-softening exponential regressive law. The FE results verify the adequacy of the cohesive zone model in accurate prediction of the interface damage behavior. The graphene/epoxy cohesive interface is characterized by normal stiffness, tensile strength, and fracture energy of 5 × 10-8 (aPa·nm-1), 9.75 × 10-10 (nm), 2.1 × 10-10 (N·nm-1) respectively, that is followed by an exponential regressive law with the exponent, α = 7.74. It is shown that the commonly assumed bilinear softening law of the cohesive interface could lead up to 55% error in the predicted separation of the interface.

Matched MeSH terms: Molecular Dynamics Simulation
Fulltext Pore formation in lipid membrane I: Continuous reversible trajectory from intact bilayer through hydrophobic defect to transversal pore

Akimov SA, Volynsky PE, Galimzyanov TR, Kuzmin PI, Pavlov KV, Batishchev OV

Sci Rep, 2017 09 22;7(1):12152.
PMID: 28939906 DOI: 10.1038/s41598-017-12127-7

Lipid membranes serve as effective barriers allowing cells to maintain internal composition differing from that of extracellular medium. Membrane permeation, both natural and artificial, can take place via appearance of transversal pores. The rearrangements of lipids leading to pore formation in the intact membrane are not yet understood in details. We applied continuum elasticity theory to obtain continuous trajectory of pore formation and closure, and analyzed molecular dynamics trajectories of pre-formed pore reseal. We hypothesized that a transversal pore is preceded by a hydrophobic defect: intermediate structure spanning through the membrane, the side walls of which are partially aligned by lipid tails. This prediction was confirmed by our molecular dynamics simulations. Conversion of the hydrophobic defect into the hydrophilic pore required surmounting some energy barrier. A metastable state was found for the hydrophilic pore at the radius of a few nanometers. The dependence of the energy on radius was approximately quadratic for hydrophobic defect and small hydrophilic pore, while for large radii it depended on the radius linearly. The pore energy related to its perimeter, line tension, thus depends of the pore radius. Calculated values of the line tension for large pores were in quantitative agreement with available experimental data.

Matched MeSH terms: Molecular Dynamics Simulation
Substrate docking and molecular dynamic simulation for prediction of fungal enzymes from Trichoderma species-assisted extraction of nanocellulose from oil palm leaves

Bahaman AH, Abdul Wahab R, Hamid AAA, Halim KBA, Kaya Y, Edbeib MF

J Biomol Struct Dyn, 2020 Sep;38(14):4246-4258.
PMID: 31608812 DOI: 10.1080/07391102.2019.1679667

Fungi of the Trichoderma species are valued industrial enzymes in support of the 'zero-waste' technology to convert agro-industrial biomass into valuable products, i.e. nanocellulose (NC). In this study, an in silico approach using substrate docking and molecular dynamic (MD) simulation was used to predict the order of which the multilayers of cellulosic polymers, i.e. lignin, hemicellulose and cellulose in oil palm leaves (OPL) are degraded by fungal enzymes, endocellulase and exocellulase. The study aimed to establish the catalytic tendencies of the enzymes to optimally degrade the cellulosic components of OPL for high yield production of NC. Energy minimized endocellulase and exocellulase models revealed satisfactory scores of PROCHECK (90.0% and 91.2%), Verify3D (97.23% and 98.85%) and ERRAT (95.24% and 91.00%) assessments. Active site prediction by blind docking, COACH meta-server and multiple sequence alignment indicated the catalytic triads for endocellulase and exocellulase were Ser116-His205-Glu249 and Ser382-Arg124-Asp385, respectively. Binding energy of endocellulase docked with hemicellulose (-6.0 kcal mol-1) was the most favourable followed by lignin (-5.6 kcal mol-1) and cellulose (-4.4 kcal mol-1). Exocellulase, contrarily, bonded favorably with lignin (-8.7 kcal mol-1), closely followed by cellulose (-8.5 kcal mol-1) and hemicellulose (-8.4 kcal mol-1). MDs simulations showed that interactions of complexes, endocellulase-hemicellulose and the exocellulase-cellulose being the most stable. Thus, the findings of the study successfully identified the specific actions of sugar-acting enzymes for NC production. Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Molecular Dynamics Simulation
Evaluating the performance of MM/PBSA for binding affinity prediction using class A GPCR crystal structures

Yau MQ, Emtage AL, Chan NJY, Doughty SW, Loo JSE

J Comput Aided Mol Des, 2019 05;33(5):487-496.
PMID: 30989574 DOI: 10.1007/s10822-019-00201-3

The recent expansion of GPCR crystal structures provides the opportunity to assess the performance of structure-based drug design methods for the GPCR superfamily. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA)-based methods are commonly used for binding affinity prediction, as they provide an intermediate compromise of speed and accuracy between the empirical scoring functions used in docking and more robust free energy perturbation methods. In this study, we systematically assessed the performance of MM/PBSA in predicting experimental binding free energies using twenty Class A GPCR crystal structures and 934 known ligands. Correlations between predicted and experimental binding free energies varied significantly between individual targets, ranging from r = - 0.334 in the inactive-state CB1 cannabinoid receptor to r = 0.781 in the active-state CB1 cannabinoid receptor, while average correlation across all twenty targets was relatively poor (r = 0.183). MM/PBSA provided better predictions of binding free energies compared to docking scores in eight out of the twenty GPCR targets while performing worse for four targets. MM/PBSA binding affinity predictions calculated using a single, energy minimized structure provided comparable predictions to sampling from molecular dynamics simulations and may be more efficient when computational cost becomes restrictive. Additionally, we observed that restricting MM/PBSA calculations to ligands with a high degree of structural similarity to the crystal structure ligands improved performance in several cases. In conclusion, while MM/PBSA remains a valuable tool for GPCR structure-based drug design, its performance in predicting the binding free energies of GPCR ligands remains highly system-specific as demonstrated in a subset of twenty Class A GPCRs, and validation of MM/PBSA-based methods for each individual case is recommended before prospective use.

Matched MeSH terms: Molecular Dynamics Simulation
Fulltext Pore formation in lipid membrane II: Energy landscape under external stress

Akimov SA, Volynsky PE, Galimzyanov TR, Kuzmin PI, Pavlov KV, Batishchev OV

Sci Rep, 2017 10 02;7(1):12509.
PMID: 28970526 DOI: 10.1038/s41598-017-12749-x

Lipid membranes are extremely stable envelopes allowing cells to survive in various environments and to maintain desired internal composition. Membrane permeation through formation of transversal pores requires substantial external stress. Practically, pores are usually formed by application of lateral tension or transmembrane voltage. Using the same approach as was used for obtaining continuous trajectory of pore formation in the stress-less membrane in the previous article, we now consider the process of pore formation under the external stress. The waiting time to pore formation proved a non-monotonous function of the lateral tension, dropping from infinity at zero tension to a minimum at the tension of several millinewtons per meter. Transmembrane voltage, on the contrary, caused the waiting time to decrease monotonously. Analysis of pore formation trajectories for several lipid species with different spontaneous curvatures and elastic moduli under various external conditions provided instrumental insights into the mechanisms underlying some experimentally observed phenomena.

Matched MeSH terms: Molecular Dynamics Simulation
Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β's activity

Homouz D, Joyce-Tan KH, Shahir Shamsir M, Moustafa IM, Idriss H

J Mol Graph Model, 2018 01;79:192.
PMID: 29223917 DOI: 10.1016/j.jmgm.2017.11.002

DNA polymerase β is a 39kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31kDa domain responsible for the polymerase activity and an 8kDa domain, which bind ssDNA and has a deoxyribose phosphate (dRP) lyase activity. DNA polymerase β was shown to be phosphorylated in vitro with protein kinase C (PKC) at serines 44 and 55 (S44 and S55), resulting in loss of its polymerase enzymic activity, but not its ability to bind ssDNA. In this study, we investigate the potential phosphorylation-induced structural changes for DNA polymerase β using molecular dynamics. The simulations show drastic conformational changes of the polymerase structure as a result of S44 phosphorylation. Phosphorylation-induced conformational changes transform the closed (active) enzyme structure into an open one. Further analysis of the results points to a key hydrogen bond and newly formed salt bridges as potential drivers of these structural fluctuations. The changes observed with S44/55 and S55 phosphorylation were less dramatic than S44 and the integrity of the H-bond was not compromised. Thus the phosphorylation of S44 is likely the major contributor to structural fluctuations that lead to loss of enzymatic activity.

Matched MeSH terms: Molecular Dynamics Simulation
Interaction of monomeric Ebola VP40 protein with a plasma membrane: A coarse-grained molecular dynamics (CGMD) simulation study

Mohamad Yusoff MA, Abdul Hamid AA, Mohammad Bunori N, Abd Halim KB

J Mol Graph Model, 2018 Jun;82:137-144.
PMID: 29730487 DOI: 10.1016/j.jmgm.2018.04.010

Ebola virus is a lipid-enveloped filamentous virus that affects human and non-human primates and consists of several types of protein: nucleoprotein, VP30, VP35, L protein, VP40, VP24, and transmembrane glycoprotein. Among the Ebola virus proteins, its matrix protein VP40 is abundantly expressed during infection and plays a number of critical roles in oligomerization, budding and egress from the host cell. VP40 exists predominantly as a monomer at the inner leaflet of the plasma membrane, and has been suggested to interact with negatively charged lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylserine (PS) via its cationic patch. The hydrophobic loop at the C-terminal domain has also been shown to be important in the interaction between the VP40 and the membrane. However, details of the molecular mechanisms underpinning their interactions are not fully understood. This study aimed at investigating the effects of mutation in the cationic patch and hydrophobic loop on the interaction between the VP40 monomer and the plasma membrane using coarse-grained molecular dynamics simulation (CGMD). Our simulations revealed that the interaction between VP40 and the plasma membrane is mediated by the cationic patch residues. This led to the clustering of PIP2 around the protein in the inner leaflet as a result of interactions between some cationic residues including R52, K127, K221, K224, K225, K256, K270, K274, K275 and K279 and PIP2 lipids via electrostatic interactions. Mutation of the cationic patch or hydrophobic loop amino acids caused the protein to bind at the inner leaflet of the plasma membrane in a different orientation, where no significant clustering of PIP2 was observed around the mutated protein. This study provides basic understanding of the interaction of the VP40 monomer and its mutants with the plasma membrane.

Matched MeSH terms: Molecular Dynamics Simulation
Fulltext In silico-based vaccine design against Ebola virus glycoprotein

Dash R, Das R, Junaid M, Akash MF, Islam A, Hosen SZ

Adv Appl Bioinform Chem, 2017;10:11-28.
PMID: 28356762 DOI: 10.2147/AABC.S115859

Ebola virus (EBOV) is one of the lethal viruses, causing more than 24 epidemic outbreaks to date. Despite having available molecular knowledge of this virus, no definite vaccine or other remedial agents have been developed yet for the management and avoidance of EBOV infections in humans. Disclosing this, the present study described an epitope-based peptide vaccine against EBOV, using a combination of B-cell and T-cell epitope predictions, followed by molecular docking and molecular dynamics simulation approach. Here, protein sequences of all glycoproteins of EBOV were collected and examined via in silico methods to determine the most immunogenic protein. From the identified antigenic protein, the peptide region ranging from 186 to 220 and the sequence HKEGAFFLY from the positions of 154-162 were considered the most potential B-cell and T-cell epitopes, correspondingly. Moreover, this peptide (HKEGAFFLY) interacted with HLA-A*32:15 with the highest binding energy and stability, and also a good conservancy of 83.85% with maximum population coverage. The results imply that the designed epitopes could manifest vigorous enduring defensive immunity against EBOV.

Matched MeSH terms: Molecular Dynamics Simulation
Molecular docking and molecular dynamics simulation of Bacillus thuringiensis dehalogenase against haloacids, haloacetates and chlorpyrifos

Oyewusi HA, Huyop F, Wahab RA

J Biomol Struct Dyn, 2020 Oct 23.
PMID: 33094694 DOI: 10.1080/07391102.2020.1835727

The high dependency and surplus use of agrochemical products have liberated enormous quantities of toxic halogenated pollutants into the environment and threaten the well-being of humankind. Herein, this study performed molecular docking, molecular dynamic (MD) simulations, molecular mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculations on the DehH2 from Bacillus thuringiensis, to identify the order of which the enzyme degrades different substrates, haloacids, haloacetate and chlorpyrifos. The study discovered that the DehH2 favored the degradation of haloacids and haloacetates (-3.3 - 4.6 kcal/mol) and formed three hydrogen bonds with Asp125, Arg201 and Lys202. Despite the inconclusive molecular docking result, chlorpyrifos was consistently shown to be the least favored substrate of the DehH2 in MD simulations and MM-PBSA calculations. Results of MD simulations revealed the DehH2-haloacid- (RMSD 0.15 - 0.25 nm) and DehH2-haloacetates (RMSF 0.05 - 0.25 nm) were more stable, with the DehH2-L-2CP complex being the most stable while the least was the DehH2-chlorpyrifos (RMSD 0.295 nm; RMSF 0.05 - 0.59 nm). The Molecular Mechanics Poisson-Boltzmann Surface Area calculations showed the DehH2-L-2CP complex (-24.27 kcal/mol) having the lowest binding energy followed by DehH2-MCA (-22.78 kcal/mol), DehH2-D-2CP (-21.82 kcal/mol), DehH2-3CP (-21.11 kcal/mol), DehH2-2,2-DCP (-18.34 kcal/mol), DehH2-2,3-DCP (-8.34 kcal/mol), DehH2-TCA (-7.62 kcal/mol), while chlorpyrifos was unable to spontaneously bind to DehH2 (+127.16 kcal/mol). In a nutshell, the findings of this study offer valuable insights into the rational tailoring of the DehH2 for expanding its substrate specificity and catalytic activity in the near future.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Molecular Dynamics Simulation
α-Mangostin and its derivatives against estrogen receptor alpha

Mardianingrum R, Yusuf M, Hariono M, Mohd Gazzali A, Muchtaridi M

J Biomol Struct Dyn, 2020 Nov 06.
PMID: 33155528 DOI: 10.1080/07391102.2020.1841031

Estrogen receptor alpha (ERα) acts as the transcription factor and the main therapeutic target against breast cancer. One of the compounds that has been shown to act as an ERα is α-mangostin. However, it still has weaknesses due to its low solubility and low potent activity. In this study, α-mangostin was modified by substituting -OH group at C6 using benzoyl derivatives through a step by step in silico study, namely pharmacokinetic prediction (https://preadmet.bmdrc.kr/adme/), pharmacophore modeling (LigandScout 4.1), molecular docking simulation (AutoDock 4.2), molecular dynamics simulation (AMBER 16) and a binding free energy analysis using MM-PBSA method. From the computational studies, three compounds which are derived from α-mangostin (AMB-1 (-9.84 kcal/mol), AMB-2 (-6.80 kcal/mol) and AMB-10 (-12.42 kcal/mol)) have lower binding free energy than α-mangostin (-1.77 kcal/mol), as evidenced by the binding free energy calculation using the MM-PBSA method. They can then be predicted to have potent activities as ERα antagonists.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Molecular Dynamics Simulation
ENRI: A tool for selecting structure-based virtual screening target conformations

Akbar R, Jusoh SA, Amaro RE, Helms V

Chem Biol Drug Des, 2017 May;89(5):762-771.
PMID: 27995760 DOI: 10.1111/cbdd.12900

Finding pharmaceutically relevant target conformations from an arbitrary set of protein conformations remains a challenge in structure-based virtual screening (SBVS). The growth in the number of available conformations, either experimentally determined or computationally derived, obscures the situation further. While the inflated conformation space potentially contains viable druggable targets, the increase of conformational complexity, as a consequence, poses a selection problem. To address this challenge, we took advantage of machine learning methods, namely an over-sampling and a binary classification procedure, and present a novel method to select druggable receptor conformations. Specifically, we trained a binary classifier on a set of nuclear receptor conformations, wherein each conformation was labeled with an enrichment measure for a corresponding SBVS. The classifier enabled us to formulate suggestions and identify enriching SBVS targets for six of seven nuclear receptors. Further, the classifier can be extended to other proteins of interest simply by feeding new training data sets to the classifier. Our work, thus, provides a methodology to identify pharmaceutically interesting receptor conformations for nuclear receptors and other drug targets.

Matched MeSH terms: Molecular Dynamics Simulation
Fulltext Lid opening and conformational stability of T1 Lipase is mediated by increasing chain length polar solvents

Maiangwa J, Mohamad Ali MS, Salleh AB, Rahman RNZRA, Normi YM, Mohd Shariff F, et al.

PeerJ, 2017;5:e3341.
PMID: 28533982 DOI: 10.7717/peerj.3341

The dynamics and conformational landscape of proteins in organic solvents are events of potential interest in nonaqueous process catalysis. Conformational changes, folding transitions, and stability often correspond to structural rearrangements that alter contacts between solvent molecules and amino acid residues. However, in nonaqueous enzymology, organic solvents limit stability and further application of proteins. In the present study, molecular dynamics (MD) of a thermostable Geobacillus zalihae T1 lipase was performed in different chain length polar organic solvents (methanol, ethanol, propanol, butanol, and pentanol) and water mixture systems to a concentration of 50%. On the basis of the MD results, the structural deviations of the backbone atoms elucidated the dynamic effects of water/organic solvent mixtures on the equilibrium state of the protein simulations in decreasing solvent polarity. The results show that the solvent mixture gives rise to deviations in enzyme structure from the native one simulated in water. The drop in the flexibility in H2O, MtOH, EtOH and PrOH simulation mixtures shows that greater motions of residues were influenced in BtOH and PtOH simulation mixtures. Comparing the root mean square fluctuations value with the accessible solvent area (SASA) for every residue showed an almost correspondingly high SASA value of residues to high flexibility and low SASA value to low flexibility. The study further revealed that the organic solvents influenced the formation of more hydrogen bonds in MtOH, EtOH and PrOH and thus, it is assumed that increased intraprotein hydrogen bonding is ultimately correlated to the stability of the protein. However, the solvent accessibility analysis showed that in all solvent systems, hydrophobic residues were exposed and polar residues tended to be buried away from the solvent. Distance variation of the tetrahedral intermediate packing of the active pocket was not conserved in organic solvent systems, which could lead to weaknesses in the catalytic H-bond network and most likely a drop in catalytic activity. The conformational variation of the lid domain caused by the solvent molecules influenced its gradual opening. Formation of additional hydrogen bonds and hydrophobic interactions indicates that the contribution of the cooperative network of interactions could retain the stability of the protein in some solvent systems. Time-correlated atomic motions were used to characterize the correlations between the motions of the atoms from atomic coordinates. The resulting cross-correlation map revealed that the organic solvent mixtures performed functional, concerted, correlated motions in regions of residues of the lid domain to other residues. These observations suggest that varying lengths of polar organic solvents play a significant role in introducing dynamic conformational diversity in proteins in a decreasing order of polarity.

Matched MeSH terms: Molecular Dynamics Simulation
Synthesis, characterization, monoamine oxidase inhibition, molecular docking and dynamic simulations of novel 2,1-benzothiazine-2,2-dioxide derivatives

Ahmad S, Zaib S, Jalil S, Shafiq M, Ahmad M, Sultan S, et al.

Bioorg Chem, 2018 10;80:498-510.
PMID: 29996111 DOI: 10.1016/j.bioorg.2018.04.012

In this research work, we report the synthesis and biological evaluation of two new series of 1-benzyl-4-(benzylidenehydrazono)-3,4-dihydro-1H-benzo[c] [1,2]thiazine 2,2-dioxides and 1-benzyl-4-((1-phenylethylidene)hydrazono)-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxides. The synthetic plan involves the mesylation of methyl anthranilate with subsequent N-benzylation of the product. The methyl 2-(N-benzylmethylsulfonamido)benzoate was subjected to cyclization reaction in the presence of sodium hydride to obtain 1-benzyl-1H-benzo[c][1,2]thiazin-4(3H)-one 2,2-dioxide which was treated with hydrazine hydrate to get corresponding hydrazone precursor. Finally, the titled compounds were obtained by reaction of hydrazone with various substituted aldehydes and ketones. The synthesized derivatives were subjected to carry out their inhibition activities against monoamine oxidases along with modelling investigations to evaluate their binding interactions and dynamic stability during the docking studies. The inhibition profile of potent compounds was found as competitive for both the isozymes. The compounds were more selective inhibitors of MAO-A as compared to MAO-B. Moreover, drug likeness profile of the derivatives was evaluated to have an additional insight into the physicochemical properties. The molecular dynamic simulations predicted the behaviour of amino acids with the active site residues.

Matched MeSH terms: Molecular Dynamics Simulation
Fulltext In silico design of potentially functional artificial metallo-haloalkane dehalogenase containing catalytic zinc

Ang TF, Salleh AB, Normi YM, Leow TC

3 Biotech, 2018 Jul;8(7):314.
PMID: 30023146 DOI: 10.1007/s13205-018-1333-9

Artificial metalloenzymes are unique as they combine the good features of homogeneous and enzymatic catalysts, and they can potentially improve some difficult catalytic assays. This study reports a method that can be used to create an artificial metal-binding site prior to proving it to be functional in a wet lab. Haloalkane dehalogenase was grafted into a metal-binding site to form an artificial metallo-haloalkane dehalogenase and was studied for its potential functionalities in silico. Computational protocols regarding dynamic metal docking were studied using native metalloenzymes and functional artificial metalloenzymes. Using YASARA Structure, a simulation box covering template structure was created to be filled with water molecules followed by one mutated water molecule closest to the metal-binding site to metal ion. A simple energy minimization step was subsequently run using an AMBER force field to allow the metal ion to interact with the metal-binding residues. Long molecular dynamic simulation using YASARA Structure was performed to analyze the stability of the metal-binding site and the distance between metal-binding residues. Metal ions fluctuating around 2.0 Å across a 20 ns simulation indicated a stable metal-binding site. Metal-binding energies were predicted using FoldX, with a native metalloenzyme (carbonic anhydrase) scoring 18.0 kcal/mol and the best mutant model (C1a) scoring 16.4 kcal/mol. Analysis of the metal-binding site geometry was performed using CheckMyMetal, and all scores for the metalloenzymes and mutant models were in an acceptable range. Like native metalloenzymes, the metal-binding site of C1a was supported by residues in the second coordination shell to maintain a more coordinated metal-binding site. Short-chain multihalogenated alkanes (1,2-dibromoethane and 1,2,3-trichloropropane) were able to dock in the active site of C1a. The halides of the substrate were in contact with both the metal and halide-stabilizing residues, thus indicating a better stabilization of the substrate. The simple catalytic mechanism proposed is that the metal ion interacted with halogen and polarized the carbon-halogen bond, thus making the alpha carbon susceptible to attack by nucleophilic hydroxide. The interaction between halogen in the metal ion and halide-stabilizing residues may help to improve the stabilization of the substrate-enzyme complex and reduce the activation energy. This study reports a modified dynamic metal-docking protocol and validation tests to verify the metal-binding site. These approaches can be applied to design different kinds of artificial metalloenzymes or metal-binding sites.

Matched MeSH terms: Molecular Dynamics Simulation
Molecular Modeling and Simulation of Transketolase from Orthosiphon stamineus

Ng ML, Rahmat ZB, Bin Omar MSS

Curr Comput Aided Drug Des, 2019;15(4):308-317.
PMID: 30345923 DOI: 10.2174/1573409914666181022141753

BACKGROUND: Orthosiphon stamineus is a traditional medicinal plant in Southeast Asia countries with various well-known pharmacological activities such as antidiabetic, diuretics and antitumor activities. Transketolase is one of the proteins identified in the leaves of the plant and transketolase is believed able to lower blood sugar level in human through non-pancreatic mechanism. In order to understand the protein behavioral properties, 3D model of transketolase and analysis of protein structure are of obvious interest.
METHODS: In the present study, 3D model of transketolase was constructed and its atomic characteristics revealed. Besides, molecular dynamic simulation of the protein at 310 K and 368 K deciphered transketolase may be a thermophilic protein as the structure does not distort even at elevated temperature. This study also used the protein at 310 K and 368 K resimulated back at 310 K environment.
RESULTS: The results revealed that the protein is stable at all condition which suggest that it has high capacity to adapt at different environment not only at high temperature but also from high temperature condition to low temperature where the structure remains unchanged while retaining protein function.
CONCLUSION: The thermostability properties of transketolase is beneficial for pharmaceutical industries as most of the drug making processes are at high temperature condition.

Matched MeSH terms: Molecular Dynamics Simulation
Fulltext Combining docking and molecular dynamic of protease from Bacillus lehensis G1

Noorul Aini Sulaiman, Nur Zazarina Ramly, Shuhaila Mat-Sharani, Nor Muhammad Mahadi

Journal of Engineering and Science Research, 2018;2(1):1-5.
MyJurnal

Protease is an enzyme that catalysed the hydrolysis of protein into peptide. Application of protease in industry has been linked with cost effective substrates and complex of enzyme-substrate stability. Molecular docking approach has identified casein as a preference substrates. However, lack of data on casein mode of binding to protease and enzyme stability represents a limitation for its production and structural optimization. In this study, we have used a molecular dynamic (MD) to examine the stability of complex enzyme-substrate of protease from Bacillus lehensis G1. The 3D structure of protease (BleG1_1979) was docked with substrate casein using AutoDock Vina. Structural analysis of the substrate-binding cleft revealed a binding site of casein was predominantly at the hydrophobic region of BleG1_1979. The MD of complex BleG1_1979-casein was tested with two temperatures; 298 K and 310 K using GROMACS v5.1.4. MD simulation showed a stable behaviour of BleG1_1979 over the 20 ns simulation period. The molecular docking and MD simulation suggested that the production of protease from B. lehensis G1 by utilization of casein and the stability of complex protease-casein could be a potential application to generate a cost effective enzyme to be develop for industrial use.

Matched MeSH terms: Molecular Dynamics Simulation
Fulltext Molecular dynamics simulations of sodium alginate/sulfonated graphene oxide membranes properties

Shaari N, Kamarudin SK, Basri S

Heliyon, 2018 Sep;4(9):e00808.
PMID: 30246163 DOI: 10.1016/j.heliyon.2018.e00808

The influence of methanol as a solvent on the properties of sodium alginate/sulfonated graphene oxide (SA/SGO) membranes was explored in water-methanol mixed conditions with various methanol concentrations and temperatures through molecular dynamics simulations. The methanol uptake of the membrane showed an isolation phase determined from the simulation results. The distance between the sulfonic acid groups increased in higher methanol concentrations, as observed from S-S RDFs. Furthermore, the distance between the SA-chain RDFs and the solvent molecules was analysed to determine a) the affinity of water towards the sulfonic acid groups and b) the affinity of the aromatic backbone of the SA towards methanol molecules. A decrease in water molecule diffusion led to an increase in methanol diffusion and uptake. SA/SGO membranes exhibited a smaller diffusion coefficient than that for the Nafion membranes, as calculated from simulation results and compared to the experimental work. Additionally, the diffusion ability increased at higher temperatures for all permeants. The interaction information obtained is useful for DMFC applications.

Matched MeSH terms: Molecular Dynamics Simulation
Molecular Dynamics Simulations of Glycyrrhizic Acid Aggregates as Drug-Carriers for Paclitaxel

Hussain M

Curr Drug Deliv, 2019;16(7):618-627.
PMID: 30868954 DOI: 10.2174/1567201816666190313155117

BACKGROUND: Glycyrrhizic acid (GA) is a glycoside that has shown considerable promise as a penetration enhancer and drug carrier to improve the absorption of poorly water-soluble drugs. The aggregation behavior of GA and its ability to form large micelles at higher solution concentrations are thought to contribute to these bioavailability enhancing properties. The oral absorption of Paclitaxel (PTX) for example, an anti-cancer agent which exhibits poor oral bioavailability, has been found to significantly increase in the presence of GA.
METHODS: In an attempt to visualize the aggregation behavior of GA and its subsequent association with PTX, 100 ns molecular dynamics simulation of a 5 mM aqueous solution of GA with 10 molecules of PTX was conducted using GROMACS and an all-atom forcefield.
RESULTS: Aggregation of GA molecules was found to occur quickly at this level of saturation leading to two stable aggregates of 13 and 17 GA molecules with an effective radius of 10.17 nm to 10.92 nm. These aggregates form not in isolation, but together with PTX molecule embedded within the structures, which reduces the number of interactions and hydrogen-bonding with water.
CONCLUSION: GA aggregation occurs around PTX molecules in solution, forming co-joined GA-PTX cluster units at a ratio of 3:1. These clusters remain stable for the remainder of the 100ns simulation and serve to isolate and protect PTX from the aqueous environment.

Matched MeSH terms: Molecular Dynamics Simulation
Molecular simulation on the stability and adsorption properties of choline-based ionic liquids/IRMOF-1 hybrid composite for selective H2S/CO2 capture

Ishak MAI, Jumbri K, Daud S, Abdul Rahman MB, Abdul Wahab R, Yamagishi H, et al.

J Hazard Mater, 2020 11 15;399:123008.
PMID: 32502857 DOI: 10.1016/j.jhazmat.2020.123008

The compatibility and performance of an Isoreticular Metal-Organic Frameworks (IRMOF-1) impregnated with choline-based ionic liquids (ILs) for selective adsorption of H2S/CO2, were studied by molecular dynamics (MD) simulation. Cholinium alanate ([Chl][Ala]) was nominated as the suitable IL for impregnation into IRMOF-1, consistent with the low RMSD values (0.546 nm, 0.670 nm, 0.776 nm) at three IL/IRMOF-1 w/w ratios (WIL/IRMOF-1 = 0.4, 0.8, and 1.2). The [Chl]+ and [Ala]- ion pair was located preferentially around the carboxylate group within the IRMOF-1 framework, with the latter interacting strongly with the host than the [Chl]+. Results of radius of gyration (Rg) and root mean square displacement (RMSD) revealed that a ratio of 0.4 w/w of IL/IRMOF-1 (Rg = 1.405 nm; RMSD = 0.546 nm) gave the best conformation to afford an exceptionally stable IL/IRMOF-1 composite. It was discovered that the IL/IRMOF-1 composite was more effective in capturing H2S and CO2 compared to pristine IRMOF-1. The gases adsorbed in higher quantities in the IL/IRMOF-1 composite phase compared to the bulk phase, with a preferential adsorption for H2S, as shown by the uppermost values of adsorption ( [Formula: see text] = 17.954 mol L-1 bar-1) and an adsorption selectivity ( [Formula: see text] = 43.159) at 35 IL loading.

Matched MeSH terms: Molecular Dynamics Simulation

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