UC Merced

Viruses have evolved multiple strategies to suppress host immune responses to improve their survival, including expressing proteins that act to mimic or inhibit components of the immune machinery. One protein produced by poxviruses, viral CC chemokine inhibitor (vCCI), is capable of binding nearly all human CC chemokines at low nanomolar to picomolar concentrations. vCCI sequesters the chemokines, blocking interaction sites necessary for binding to their cognate receptors, and thus disrupting immune signaling. Understanding vCCI’s remarkable ability to bind specifically to such a diverse set of chemokines would increase our knowledge of both the immune system and viral strategies to evade it. Additionally, the ability to engineer vCCI analogs could open the door to a new class of anti-inflammatory drugs.We used MD simulations of vCCI bound to several CC chemokines and the herpesvirus HHV8 decoy chemokine vMIP-II to reveal how vCCI manages both specificity and breadth of its interactions with members of the CC chemokine family. Along with key hydrophobic interactions and salt bridges between vCCI and the chemokines, we identified an additional beta strand formed along the CC chemokine N loop, which has previously been found for other chemokine binding proteins but not reported for vCCI. Further building on these models, we simulated published vCCI mutations, such as the Y80A loss of function, to identify a plausible cause of the loss of function through acidic loop collapse due to the loss of the bulky residue. Finally, we used these results to generate new hypotheses of other mutations to “tune” the binding of vCCI, to be tested by further experiments.