Brief overview of Immunology and Molecular Dynamics

Denise Chac10 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

• 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

cells

B Cell

T-Cells

Viruses

HIV/AIDS

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]

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 proteins

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 coordinates• Velocities

– Protein Structure File – PSF• Structural information

– Force Field Parameter File• Mathematical potential of

atoms in the system

– Configuration File• Tells how NAMD will run the

simulation

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 conditions

Questions:

• “epitope enhancement”• Difference between R5 and X4 HIV• TCR flexibility [Martinez-Hackert et al. 2006]

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. 4th Edition. New York: Garland Science.

• Janeway, C., Murphy, K., Travers, P., Walport, M. 2008. Janeway’s Immunobiology. 8th Edition. New York: Garland Science .