Shuju Bai

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.

MapReduce-Based RESTMD: Enabling Large-Scale Sampling Tasks with Distributed HPC Systems

A novel implementation of Replica Exchange Statistical Temperature Molecular Dynamics (RESTMD), belonging to a generalized ensemble method and also known as parallel tempering, is presented. Our implementation employs the MapReduce (MR)-based iterative framework for launching RESTMD over high performance computing (HPC) clusters including our test bed system, Cyber-infrastructure for Reconfigurable Optical Networks (CRON) simulating a network-connected distributed system. Our main contribution is a new implementation of STMD plugged into the well-known CHARMM molecular dynamics package as well as the RESTMD implementation powered by the Hadoop that scales out in a cluster and across distributed systems effectively. To address challenges for the use of Hadoop MapReduce, we examined contributing factors on the performance of the proposed framework with various runtime analysis experiments with two biological systems that differ in size and over different types of HPC resources. Many advantages with the use of RESTMD suggest its effectiveness for enhanced sampling, one of grand challenges in a variety of areas of studies ranging from chemical systems to statistical inference. Lastly, with its support for scale-across capacity over distributed computing infrastructure (DCI) and the use of Hadoop for coarse-grained task-level parallelism, MapReduce-based RESTMD represents truly a good example of the next-generation of applications whose provision is increasingly becoming demanded by science gateway projects, in particular, backed by IaaS clouds.

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.

Implementing replica exchange molecular dynamics using work queue

Replica exchange molecular dynamics (REMD) has been used by researchers to improve sampling rates in molecular dynamics simulations. In traditional t-REMD, individual replicas run in parallel at different temperatures. The neighboring replicas exchange temperature based on a criterion after a time interval. In this research, we implemented REMD on a computational framework, Work Queue, and evaluated the performance of Work Queue based REMD. The master-worker architecture was used in our implementation. All replicas were assigned to workers, outputs from replicas on workers were gathered and sent to the master and processed on the master. NAMD was used to carry out individual molecular dynamics simulations. The programming language used in the implementation was C. We evaluated the performance of Work Queue based REMD. The experimental results demonstrate linear scalability for lower number of replicas.

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.

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.

Using computational method to identify the binding site of 8R-lipoxygenase for arachidonic acid

Lipoxygenases (LOX) play important roles in the biosynthesis of biologically active eicosanoids form polyunsaturated fatty acids. An understanding of the structure basis of LOX familiy is critical for the development of LOX specific inhibitors. In this study, a computational method, Internal Coordinate Mechanics (ICM) was applied to find the binding site of 8R-LOX for its substrate, arachidonic acid (AA). The docking simulation shows that the C-10 of AA is positioned against Fe, which is in favor of the catalytic process of 8R-LOX. A potential binding site is defined. The purpose of this study is to identify the binding site using computational method. The result helps model how the arachidonic acid binds in the active site of LOX super family.