Human immunodeficiency virus (HIV) infection of T-cells begins when the viral envelope glycoprotein, gp120, binds to CD4 receptors on the target cell surface. Over the past several years, proteins isolated from various prokaryotes have been shown to inhibit HIV cell entry by binding to gp120 and thus blocking the association with CD4. Lectins that bind to high-mannose oligosaccharides on gp120 are an attractive class of antiviral agents. While several of these have been quite well characterized both structurally and biochemically, there remain many open questions regarding their mechanism of inhibition. Among the best studied is cyanovirin-N (CVN), which is currently under clinical study for use as a topical prophylactic. Large-scale molecular dynamics simulations have identified important structural features of this system that are difficult to resolve experimentally, and binding free energies of a diverse set of oligosaccharide targets computed from these structural ensembles give remarkable agreement with experiment. Detailed decompositions of the binding free energies on a residue-by-residue basis have additionally identified several key interactions that define broad affinity for &alpha -(1,2)-dimannose-containing sugars, as well as a number of determinants of specificity. These studies provide a deeper understanding of the mechanism of inhibitory activity. In addition, this work has provided a foundation for methodological improvements that allow us to more accurately capture the energetics of carbohydrate binding.