Denise Chac 10 October 2014 Immunology The study of the human immune system Lymphocytes B Cells Membrane bound antibody Activation bind to pathogen and triggered by helper T cells MHC II proteins present antigen peptide on cell surface ID: 441825
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Slide1
Brief overview of Immunology and Molecular Dynamics
Denise Chac
10 October 2014Slide2
Immunology
The study of the human immune system Slide3
Lymphocytes
B Cells
Membrane bound antibody
Activation: bind to pathogen and triggered by helper T cells
MHC II proteins present antigen peptide on cell surface
Differentiates
Effector Cells
Memory Cells
T Cells
T Cell Receptors (TCR)
Helper T Cells
Presents CD4
Recognize MHC class II
Activation: release of cytokines
Cytotoxic T Cells
Presents CD8
Recognizes MHC class I
Destroys infected/cancerous cellsSlide4
B CellSlide5
T-CellsSlide6
VirusesSlide7
HIV/AIDSSlide8
Previous Studies
The breadth of epitope recognition within specific regions of HIV antigen peptides contribute to anti-viral efficiency of CD8 T-cell response [
Geldmacher
et al. 2007]
The altering of antigen peptides on MHC to give a more ‘protruding’ surface topology may increase TCR repertoire diversity [Turner et al. 2005]Slide9
Method: Molecular Dynamics
VMD – Visual Molecular Dynamics
Program to visualize large biomolecular systems in 3-D graphics
Molecular Dynamics - NAMD
MODELLER
Homology studies
Python based homology modeling software used for modeling proteinsSlide10
Methods: NAMD
Parallel molecular dynamics code designed for high-performance simulation of large biomolecular systems
Based on Charm++ but can be
compatible
with AMBER, CHARMM, and X-PLOR
Need:
Protein Data Bank – PDB
Atomic
coordinatesVelocitiesProtein Structure File – PSF
Structural information
Force Field Parameter File
Mathematical potential of atoms in the system
Configuration File
Tells how NAMD will run the simulationSlide11
Methods: NAMD – the solvent
Put protein in water to resemble the cellular environment
How?
A water sphere in surrounding vacuum
Without periodic boundary conditions
A water box
With periodic boundary conditionsSlide12
Questions:
“epitope enhancement”
Difference between R5 and X4 HIV
TCR flexibility [Martinez-
Hackert
et al. 2006]Slide13
References
Martinez-
Hackert
, E.,
Anikeeva
, N.,
Kalams
, S.A., Walker, B.D., Hendrickson, W.A., Sykulev, Y., 2006. Structural basis for degenerate recognition of natural HIV peptide variants by cytotoxic lymphocytes. Journal of Biological Chemistry 281, 20205–20212. Geldmacher, C., Currier, J.R., Herrmann, E., Haule
, A., Kuta, E., McCutchan, F.,
Njovu
, L.,
Geis
, S., Hoffmann, O.,
Maboko
, L., Williamson, C.,
Birx
, D.,
Meyerhans
, A., Cox, J.,
Hoelscher
, M., 2007. CD8 T-cell recognition of multiple epitopes within specific Gag regions is associated with maintenance of a low steady-state
viremia
in human immunodeficiency virus type 1-seropositive patients. Journal of Virology 81, 2440–2448
.
Turner
, S.J.,
Kedzierska
, K.,
Komodromou
, H., La
Gruta
, N.L.,
Dunstone
, M.A., Webb, A.I., Webby, R., Walden, H.,
Xie
, W.,
McCluskey
, J., Purcell, A.W.,
Rossjohn
, J., Doherty, P.C., 2005. Lack of prominent peptide–major histocompatibility com-
plex
features limits repertoire diversity in virus-specific CD8+ T cell populations. Nature Immunology 6, 382–389.
Park, M., Park, S.Y., Miller, K.R., Collins, E.J., Lee, H.Y., 2013. Accurate Structure prediction of peptide-MHC complexes for identifying highly immunogenic antigens. Molecular Immunology 56, 81-90.
Alberts
, B., Johnson, A., Lewis, J. et al. 2002. Molecular Biology of the Cell. 4
th
Edition. New York: Garland Science.
Janeway
, C., Murphy, K., Travers, P.,
Walport
, M. 2008.
Janeway’s
Immunobiology
. 8
th
Edition. New York: Garland Science .