Prediction of CD28-CD86 protein complex structure using different level of resolution approach

Immune system plays essential role in functioning of higher organisms. Its hyperactivity can lead to autoimmune diseases or even anaphylactic shock while hypoactivity leads to proneness to infections or even cancer. T-cells play crucial role in immunity mechanisms and their activation and inhibition is strictly controlled by the regulatory proteins, such as CD28 and CTLA-4. Activity of these proteins is controlled by a pair of ligands, named CD80 and CD86, which can non-covalently bound to their receptors. While structure of human CTLA-4-CD86 complex in known, there is still no available structure for the CD28-CD86 system. To obtain the reliable structure of CD28-CD86 complex we first validated our methodology on the CTLA-4-CD86 system. Then coarse-grained UNRES-dock molecular docking simulation was performed followed by all-atom molecular dynamics simulations. As a result, we obtained a complete CD28-CD86 complex structure on atomistic level, in which interaction interface is consistent with available data. We also determined the kinetic properties for CTLA4-CD86 and CD28-CD86 complexes with use of coarse-grained model and determined the key residues for complex formation with use of Robetta, PPCheck and HawkDock servers. Our results not only verify high accuracy of the UNRES-dock method, but also provide a highly reliable model of the CD28-CD86 complex, which can be used in further studies and drug design.