Residue-residue contact prediction in the HIV-1 envelope glycoprotein complex

HIV-1 Env glycoprotein complex is the key protein that mediates binding and entry of HIV-1 into human host cells. The complex entry process involves three main steps. First, the attachment, the interaction of gp120 and CD4. Second, the coreceptor binding, where gp120 binds the chemokine receptor CCR5 or CXCR4, and finally, the fusion of viral and host cell membranes. Despite the fact that several coordinate structures of HIV-1 Env in unliganded state exist (as well as in complex with CD4, CD4 mimics, or various antibodies, and of gp41 in intermediate and post-fusion state), a comprehensive understanding of structural arrangements and communication within gp120 and gp41 domains during the entry is far from complete. In this study, we applied a direct amino acid interaction detecting method to analyse the function and structure of HIV-1 Env protein sequences representing all group M subtypes. We identified more than 400 coevolving residue pairs within Env, of which the majority are real contacts and proximal in the available coordinate structures, or have functional implications such as receptor binding, variable loop, gp120-gp41, and interdomain interactions. This work provides a new dimension of information in HIV research, important in assisting protein coordinate structure prediction and in designing new and effective entry inhibitors.