Ebrahim Khosravi

Applying internal coordinate mechanics to model the interactions between 8R-lipoxygenase and its substrate

BackgroundLipoxygenases (LOX) play pivotal roles in the biosynthesis of leukotrienes and other biologically active potent signalling compounds. Developing inhibitors for LOX is of high interest to researchers. Modelling the interactions between LOX and its substrate arachidonic acid is critical for developing LOX specific inhibitors. Currently, there are no LOX-substrate structures. Recently, the structure of a coral LOX, 8R-LOX, which is 41% sequence identical to the human 5-LOX was solved to 1.85Å resolution. This structure provides a foundation for modelling enzyme-substrate interactions.MethodsIn this research, we applied a computational method, Internal Coordinate Mechanics (ICM), to model the interactions between 8R-LOX and its substrate arachidonic acid. Docking arachidonic acid to 8R-LOX was performed. The most favoured docked ligand conformations were retained. We compared the results of our simulation with a proposed model and concluded that the binding pocket identified in this study agrees with the proposed model partially.ResultsThe results showed that the conformation of arachidonic acid docked into the ICM-identified docking site has less energy than that docked into the manually defined docking site for pseudo wild type 8R-LOX. The mutation at I805 resulted in no docking pocket found near Fe atom. The energy of the arachidonic acid conformation docked into the manually defined docking site is higher in mutant 8R-LOX than in wild type 8R-LOX. The arachidonic acid conformations are not productive conformations.ConclusionsWe concluded that, for the wild type 8R-LOX, the conformation of arachidonic acid docked into the ICM-identified docking site is more stable than that docked into the manually defined docking site. Mutation affects the structure of the putative active site pocket of 8R-LOX, and leads no docking pockets around the catalytic Fe atom. The docking simulation in a mutant 8R-LOX demonstrated that the structural change due to the mutation impacts the enzyme activity. Further research and analysis is required to obtain the 8R-LOX-substrate model.

A Hadoop approach to advanced sampling algorithms in molecular dynamics simulation on cloud computing

Cloud computing has emerged as a prevalent computing paradigm with the advantages of virtualization, scalability, fault tolerance, and a usage based pricing model. It has been widely used in various computational research fields. Replica exchange molecular dynamics (REMD) and replica exchange statistical temperature molecular dynamics (RESTMD) are two sampling algorithms in molecular dynamics. Due to the inherent parallel feature of REMD and RESTMD, it is practical to convert them into cloud computing applications. However, the performance of REMD and RESTMD on clouds has not been extensively investigated. In our work, we implemented REMD and RESTMD in cloud computing environment through Hadoop, an open source implementation of MapReduce platform, and evaluated the performance of REMD and RESTMD in cloud computing environment and in high performance computing (HPC) environment as reference. In our research, REMD and RESTMD exhibits good feasibility in cloud computing. Otherwise, cloud computing demonstrates the characteristics of virtualization, elasticity, and scalability, providing a robust environment for REMD and RESTMD.

Structural and mechanical stability of dilute yttrium doped chromium

Rare earth element doping of chromium is much desired for various applications, but is technically difficult because of dopant segregation. Using a room temperature mechanical alloying method, dilute yttrium doping into nanosized chromium was achieved. Synchrotron-based high-pressure X-ray diffraction indicated that the Cr-Y alloy (Cr0.97Y0.03) was stable at up to 39 GPa, and the bulk modulus was 203 ± 2.6 GPa. The experimental results were consistent with first-principles density functional theory simulation. The diffraction line broadening profiles indicated the deformation anisotropy of the nanoalloy. This study suggests that Cr0.97Y0.03 alloy is promising for ultrahigh stress applications such as airplane engines and land-based turbines.

Docking arachidonic acid to 8R-lipoxygenase using internal coordinate mechanics

Human lipoxygenases (LOX) play important roles in the biosynthesis of leukotrienes which contribute to inflammation in asthma and bronchitis. Specific inhibitors that can modulate the physiological and pathological effects of these potent signaling compounds are of high interest. Currently, there are no human LOX structures that provide a model for how the substrate, arachidonic acid (AA) binds in the LOX active site, a model critical for the development of LOX specific inhibitors. The 1.85Å resolution structure of a coral LOX, 8R-LOX, with 41% sequence identity to the human arachidonate 5-LOX, provides a strong foundation for modeling enzyme-substrate interactions. In this research, a computational approach, Internal Coordinate Mechanics (ICM) was applied to simulate the interactions between 8R-LOX and its substrate, arachidonic acid. Docking of AA into wide type 8R-LOX and mutant 8R-LOX was performed with various settings. Various docking confirmations of AA were obtained. The most favored docked ligand conformations with the lowest free energy were retained. The simulation data is consistent with experimental data. These ligand conformations help to define the binding site residues in 8R-LOX and model how the arachidonic acid binds in the active site of LOX super family.

Computational Design and Experimental Validation of New Thermal Barrier Systems

This project (10/01/2010-9/30/2014), “Computational Design and Experimental Validation of New Thermal Barrier Systems”, originates from Louisiana State University (LSU) Mechanical Engineering Department and Southern University (SU) Department of Computer Science. This project will directly support the technical goals specified in DE-FOA-0000248, Topic Area 3: Turbine Materials, by addressing key technologies needed to enable the development of advanced turbines and turbine-based systems that will operate safely and efficiently using coal-derived synthesis gases. In this project, the focus is to develop and implement novel molecular dynamics method to improve the efficiency of simulation on novel TBC materials; perform high performance computing (HPC) on complex TBC structures to screen the most promising TBC compositions; perform material characterizations and oxidation/corrosion tests; and demonstrate our new thermal barrier coating (TBC) systems experimentally under integrated gasification combined cycle (IGCC) environments.

An MPI-enabled MapReduce framework for molecular dynamics simulation applications

Computational technologies have been extensively investigated to be applied into many application domains. Since the presence of Hadoop, an implementation of MapReduce framework, scientists have applied it to biological sciences, chemistry, medical sciences, and other areas to efficiently process huge data sets. Although Hadoop is fault-tolerant and processes data in parallel, it does not support MPI in computing. The Map/Reduce tasks in Hadoop have to be serial, which results in inefficient scientific computations wrapped in Map/Reduce tasks. In the real world, many applications require MPI techniques due to their nature. Molecular dynamics simulation is one of them. In our research, we proposed a MPI-enabled MapReduce framework for molecular dynamics simulation applications. The MPI module added into Hadoop enables Hadoop to monitor and manage the resources of a Hadoop cluster so that computations incurred in Map tasks can be performed over available resources on the cluster in a parallel manner. We evaluated the proposed framework against a molecular dynamics simulation algorithm, RESTMD, with the application software CHARMM. The experimental results showed that the MPI-enabled framework improves computing efficiency in molecular dynamics simulation.

ELECTRONIC STRUCTURE OF K0.8Fe2Se2 FROM DENSITY FUNCTIONAL THEORY GW METHOD SIMULATION

First principles density functional theory — based (GW) method — was used to simulate the electronic structure of the novel iron-based superconductor K0.8Fe2Se2. The calculated band gap of K0.8Fe2Se2 at the Γ point is 0.15 eV, which is significantly lower than the 0.61 eV of vacancy free crystal KFe2Se2. The d-orbital of Fe atom is overlapped with the p-orbital of Se atom. Charge density analysis shows strong lattice distortion and vacancy related electric dipole and quadruple near the K vacancy. The reflectivity is anisotropic in three coordinate directions.

Docking arachidonic acid into human 5/12-lipoxygenase using ICM

Lipoxygenases(LOX) are a super gene family of iron-containing enzymes, that catalyze the stereo- and regio-specific formation of fatty acid hydroperoxides from polyunsaturated fatty acids. Mammalian lipoxygenase have been implicated in the pathogenesis of various inflammatory responses. An increasing number of researchers and scholars focus on developing the specific inhibitors for LOX. Due to the important role the LOX play, modeling the interaction between substrate arachidonic acid (AA) and lipoxygenase is of great significance. In this research, we modeled the interactions between 5-LOX/12LOX and their substrate AA. The crystal structure of human 5-LOX and 12-LOX were obtained from protein data bank. Internal Coordinated Mechanics (ICM) was used to perform the docking.

Interaction simulation of Lipoxygenase with arachidonate acid using NAMD

Lipoxygenase (LOX) family is believed as the major cause of pathological symptoms in asthma by biosynthesis of leukotrienes. The physiological function is known as firstly producing 8R-HPETE (derived from arachidonate acid, referred as AA), which is transformed in further enzymatic step into leukotrienes. However, much less detail is known about the role of 5-Lox in the inflammatory reaction. We have used the 1.85Å resolution structure of a wild coral Lipoxygenase (8R-LOX) (with 41% sequence identical to the human arachidonate 5-LOX) as a foundation to model the interactions between 8R-Lox and its substrate AA, and its binding site was identified using ICM. In this research, the 8R-Lox:AA complex obtained was refined and analyzed by molecular dynamic method (NAMD). Parameterization scheme for unknown structure of non-heme iron ligated by a series of residues was developed using VMD paratool plugin. All quantum mechanical calculation were performed by Gaussian03 with the Becke3LYP functional at 6–31G(d) basis set.

Dioxygen adsorption and dissociation on nitrogen doped carbon nanotubes from first principles simulation

The electronic and materials properties of carbon nanotubes (CNTs), like those of recent discovered graphene and earlier found fullerenes, attracted lots of research interests due to their appealing applications1 in the field of molecular electronics or for the refinement of materials, such as antistatic paints and shieldings, sensor, and catalytic functionality in fuel cells, etc. Like its two/three dimensional siblings graphene and graphite, CNTs consist sp2 hybridized carbon atoms and are either semiconducting or metallic depending on their helicity. CNTs can be considered in structure as rolling up a single sheet of graphene into a cylinder. Polymer electrolyte membrane fuel cells (PEMFCs) are the best candidates for automobile propulsion owing to their zero emissions, low temperature, and high efficiency. Precious platinum (Pt) catalyst is a key ingredient in fuel cells, which produce electricity and water as the only byproduct from hydrogen fuel.2 However, platinum is rare and expensive. Reducing the amount of Pt loading by identifying new catalysts is one of the major targets in the current research for the large-scale commercialization of fuel cells. Specifically, developing alternative catalysts to substitute platinum for the oxygen reduction reaction (ORR) in the fuel cell cathodes is essential because the slow kinetics of this reaction causes significant efficiency losses in the fuel cells. Recent intensive research efforts in reducing or replacing Pt-based electrode in fuel cells have led to the development of new ORR electrocatalysts, including carbon nanotube–supported metal particles.3,4 In 2006, Ozkan and coworkers reported that nitrogen-containing nanostructured carbons and nanotubes have promising catalytic activity towards ORR.5,6 In a 2008 report, Yang et al. at Argonne National Laboratory showed that the vertically-aligned CNT arrays, which are functionalized through nitrogen and iron doping by a chemical vapor deposition (CVD) process, can be electrocatalytically active toward ORR.7 The functionalized CNTs show promise properties as an alternative non-Pt electrocatalyst with a unique nano-architecture and advantageous material properties for the cathode of PEMFC. They further identified FeN4 sites, which are incorporated into the graphene layers of aligned carbon nanotubes, being electrocatalytic active towards ORR, by their X-ray absorption spectroscopy and other characterization techniques.