Molecular Dynamics Simulation Studies of Membrane Bilayers of Lipid a from Various Gram-Negative Bacteria

Molecular Dynamics Simulation Studies of Membrane Bilayers of Lipid a from Various Gram-Negative Bacteria

Monday, February 29, 2016 oligosaccharides of the ganglioside extend out from the cell surface, interacting with various signaling molecules. Some of ...

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Monday, February 29, 2016 oligosaccharides of the ganglioside extend out from the cell surface, interacting with various signaling molecules. Some of their functions include regulation of protein activities, recognition of specific molecules, and communication between cells. Gangliosides are especially abundant in the brain, with three times as much in grey as in white matter. It is believed that gangliosides are involved in pathological states such as cancer, Tay-Sachs disease, Huntington’s disease, Alzheimer’s disease, et certera. To explore and understand the orientation, structure, and dynamics of gangliosides, molecular dynamics simulations on 41 different types of gangliosides in homogenous membrane bilayer were performed. CHARMM-GUI was utilized to build the membrane bilayers, and a ganglioside was inserted in both the upper leaflet and the bottom leaflet, with three simulations for each ganglioside. Future work includes assembling the information gathered through multiple analyses for greater understanding of gangliosides, which will aid in glycome studies. 1585-Pos Board B562 Molecular Dynamics Study of Ganglioside GM3/DPPC Membrane by Using Coarse-Grained Model Kento Inoue1, Eiji Ymamoto1, Daisuke Takaiwa1, Kenji Yasuoka1, Masuhiro Mikami2. 1 Yasuoka Laboratory, Department of Mechanical Engineering, Keio University, Yokohama, Japan, 2Graduate School of Science and Technology, Keio University, Yokohama, Japan. Lipid raft is microdomain consisting of sphingomyelin, cholesterol, and glycosphingolipids, which provides unique membrane environments for various biological reactions such as adhesion of cells, regulation of membrane proteins, and virus infection. Lipid bilayer membrane including glycosphingolipids is useful as a model membrane of the complex bio-membrane. In this study, we investigate the structural properties of hydrated ganglioside GM3/dipalmitoylphosphatidycoline (DPPC) membrane depending on the concentration of glycosphingolipid molecules (0, 5, 10, 20 mol %) by using coarse-grained molecular dynamics simulations. The model membranes consisting of 1500 lipids were constructed and simulations were run for 10 microsecond. We observed the formation of raft-like lipid microdomains. We present the effect of these microdomains on the lipid membrane properties, such as order parameter, membrane thickness, area per lipid, and lateral diffusivity of lipids. 1586-Pos Board B563 Molecular Dynamics Simulation Studies of Lipopolysaccharide Micelles Pushpa Itagi, Wonpil Im. Center for Computational Biology, University of Kansas, Lawrence, KS, USA. A lipopolysaccharide (LPS) is one of the major structural components of the outer membrane in gram-negative bacteria. LPS, an amphipathic molecule, consists of a hydrophobic lipid (Lipid A) and a large hydrophilic polysaccharide composed of a core oligosaccharide and an O-antigen polysaccharide. LPS plays an important endotoxic role and it can activate the host immune system. LPS tends to form micelles when it reaches a threshold concentration, therefore it is important to understand the aggregation properties of these LPS micelles. In our studies, we have used two cores of Escherichia coli LPS (R1 and K12) and performed molecular dynamics simulations of homogenous LPS-only micelles (without O-antigen) in water. The simulation results are discussed in terms of micelle density distributions of individual components, micelle shapes, radius of gyration, and other structural properties. 1587-Pos Board B564 Molecular Dynamics Simulation Studies of Membrane Bilayers of Lipid a from Various Gram-Negative Bacteria Seonghoon Kim, Wonpil Im. Center of Bioinformatics, Lawrence, KS, USA. Lipid A is a lipid component of a lipopolysaccharide (LPS) in the outer leaflet of the outer membrane of gram-negative bacteria. Lipid A plays an important role as an LPS anchor to the outer membrane using its several acyl chains, and its structure is also important to bacterial pathogenesis and membrane integrity. Thus, the considerable efforts have been made to identify structural features of lipid A from various gram-negative bacteria. In general, lipid A consists of two phosphorylated N-acetyl glucosamine and several acyl chains which are directly linked to the two sugars. Depending on the bacterial species, acyl chain varies in length and number. Also, some bacterium can have multiple lipid A types and further be substituted by residues such as L-Ara4N or peptide. In this work, homogeneous lipid bilayers using 23 distinctive lipid A types from 15 bacterial species are modeled and simulated to investigate the differences and similarities of the membrane properties. In addition, the models at different ion type are built to examine the ion’s influence on the membrane properties.

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1588-Pos Board B565 Self Assembly of Disordered Folded Multiphase Proteins by Computer Simulations Eduardo R. Cruz-Chu1, Konstantinos Gkagkas2, Frauke Graeter1. 1 MBM, HITS, Heidelberg, Germany, 2R&D Advanced Technology Division 2, Toyota Motor Europe, Zaventem, Belgium. Disordered proteins have the capacity to self-assemble from random coils to partial or complete folded structures. Such combination of amorphous/ordered phases within the protein structure is determined by the aminoacid sequence as well as enviromental factors, such as flow or confinement, and it is expected that the proportion of each phase would play a role in the activity and biological function of the protein. Nevertheless, modeling the molecular arrangement of disordered/folded structures poses a challenge and it has been possible only for few short fragments or individual proteins. For macromolecular complexes, computationally analyzing properties such as dynamics, mechanics or heat transfer requires taking the polymeric nature of chain entanglements into account. We devised a new approach based on an existing collapsing-annealing Molecular Dynamics protocol [1] for building amorphous phases of long disordered protein chains. We adapted it to also include structured phases such as beta-sheet units, by steering parts of the protein chains into the experimentally known conformations. As a proof-of-concept, we successfully set up a model of 100 intrinsically disordered chains each comprising 500 aminoacids of silk spidroin. This resulted in a compact protein-only system (20 nm)^3 in size. Then, we introduced silk crystalline units based on x-ray scattering data, highlighting that our newly-develop protocol can handle composite materials with partial structure as well. Our full detail atomistic structure is the most comprehensive silk model computationally studied to date, up to our knowledge. We believe our approach to be valuable for a wide range of Molecular Dynamics simulations, in which the disordered polymeric component of proteins dominates in the assembly or biomaterial. [1] Cruz-Chu, E. R et al. Faraday Discussions (2009) 143, 47-62. 1589-Pos Board B566 Rational Methods to Pharmacologically Target IDPs: Developing Modulators of Tau Aggregation David W. Baggett. Medicinal Chemistr, University of Washington, Seattle, WA, USA. Despite a large amount of time and effort invested, the development of drugs targeting intrinsically disordered proteins (IDPs) is a major open problem in pharmacology. Classic drug development strategies are impeded by the highly dynamic nature of IDPs. We propose a strategy to identify inhibitors of the pathological aggregation of the IDP tau, implicated in Alzheimer’s disease and other neurodegenerative disorders. We approach this problem by utilizing computational approaches and in vitro experiments to develop new modulators of tau aggregation as discussed below. Initially, computational simulations were used to generate conformational ensembles of tau244-372, the aggregation-prone microtubule binding region of tau. For this purpose, conventional molecular dynamics (MD) simulations were compared against enhanced sampling methods, including a recently developed novel approach based on repeated simulated annealing (ReSA). Preferentially sampled conformations within these dynamic ensembles were identified based on local and global structural similarity. To do this, the structures were grouped together based on root mean standard deviations (RMSD) between conformations and representative structures then generated from these groups. Subsequent computational screening identified selective ligands of these preferentially sampled structures by creating receptor force-fields from the representative structures and scoring potential ligand affinity based on steric, electrostatic and hydrophobic properties. Finally, computational hits were validated using a variety of biophysical methods including fibril-formation assays and single-molecule fluorescence approaches such as fluorescence correlation spectroscopy. This strategy has the potential to enhance our ability to rationally target IDPs for pharmacological intervention and may prove valuable in tackling other IDP-related pathologies such as Parkinson’s disease, Diabetes, and Huntington’s disease. 1590-Pos Board B567 Structural Studies of Fibril Formations of Tetrapeptides Using Replica Exchange Molecular Dynamics Simulations Yoshitake Sakae, Yuko Okamoto. Physics, Nagoya University, Nagoya, Japan. Amyloid fibrils are peptide or protein aggregates, which are found in about 20 diseases such as Alzheimer’s disease, transmissible spongiform