The aim of this proposal is to understand the structural and biophysical basis for the effect of opioids on HIV expression. Some chemokine receptors are cofactors for HIV infection, but little is known about the mechanism involved, or how opioids modulate the interaction of HIV with these receptors. Methods of molecular modeling and theoretical computations will be applied to build models of the chemokine receptors and to analyze their interactions with chemokines, HIV and opioids. The long term goal of this proposal is to use these models to aid the design of novel opioid ligands aimed at regulating immune function and HIV expression. Models of chemokine receptors used by HIV for viral fusion will be built using methods appropriate for modeling of G protein-coupled receptors (GPCR). These will include both established and novel techniques suitable for the studies of transmembrane proteins. Extensive conformational studies will be conducted on the extracellular regions that are important for the binding of chemokines and HIV. Molecular dynamics simulations of the models will be performed using novel techniques aimed at characterizing conformational changes relevant to receptor activation. Homology modeling techniques will be applied to generate models of pertinent chemokines and of the V3 loop of the HIV envelope protein gp120. Binding of chemokines to the modeled receptors will make use of computations of the electrostatic interaction energy to identify complementary regions between chemokines and their receptors. The binding of the V3 loop of the HIV envelope protein will also be examined to analyze possible similarities with the binding mode of chemokines. Endogenous opioid peptides have many of the properties of chemokines, including chemotaxis. Furthermore, opioid and chemokine receptors share high sequence homology within the family of GPCR. Little is known, however, on how the chemokine and opioid systems interact with each other. Specifically, we will compare chemokine and opioid receptors models to rationalize structural and physical similarities that could result in the binding of opioid ligands to chemokine receptors. The receptor models will be used to study the binding of immunoregulatory opioid ligands.
