The main role of Class-I HLA molecules is to present peptides on the cell surface to T-cell receptors (TCRs). When a TCR interacts with a HLA protein (HLA-A*24 in the video), both the HLA-A amino acids (AAs), and other aminoacids from the presented peptide make direct contacts to the TCR. The presented peptides are usually small (8-10 AA long) fragments derived from proteins of the cell. These proteins are the "normal" ones building up the cells, and the presented small peptides everywhere on the the surface of each of our cells. Once a pathogen (bacterium/virus) manages to enter to the cell, its peptides will also be presented on the cell surface. These peptides are expected to be different from the host's peptides (as proteins building up viruses and bacteria are different) the pattern on the surface of the HLA protein will be also different - this is what the T-cell receptor will recognize as "foreign". On this animation the 3VXR crystal structure shows that principal interactions in the HLA-peptide-TCR complex. You can see that the peptide (a piece from the HIV virus) is not completelly buried in the HLA-A protein, there are amino acids dangling into the intercellular space, and these can make direct interactions (H-bonds, pi-pi stackings, van der Waals) with the corresponding amino acids of the T-cell receptor. There are important water molecules as well, these are not visualized to make the picture less cluttered. These interactions are governed by the density of electrons around different atom types. The electrostatic potential around this ramified structure can be estimated using Poisson-Boltzmann electrostatics, and visualized by PyMOL. Amino acids building up proteins are generally polar molecules (though many has apolar sidechains), therefore when calculating electrostatic potentials, one have to consider the polar water molecules solvating the protein. Electrostatic potential differences in the binding region depict those patterns that are responsible for the binding of the HLA and TCR molecules. Most of the surface shown is gray (water is surrounding the proteins) the colourful patterns in and around the binding cleft are what a T-cell receptor can recognize as an epitopes. _______________________________________________________ Animation by pymol (www.pymol.org) Electrostatics by APBS (www.poissonboltzmann.org) Created by Szilveszter Juhos, Senior Scientist, Omixon. For more information, contact support@omixon.com Visit the Omixon Academy website: www.omixon.com/omixon-academy-home/

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