The hydrophobic pocket within the coiled coil domain of HIV-1 gp41 is considered to be a hot-spot suitable for small molecule intervention of fusion, although so far it has yielded only microM inhibitors. Previous peptide studies have identified specific hydrophobic interactions and a Lys-Asp salt bridge as contributing to binding affinity in the pocket. Negative charge appears to be critical for activity of small molecules. We have examined the role of charge and amphiphilic character in the interaction by studying a series of short pocket binding peptides differing in charge, helical content, and in the presence or absence of the Lys-Asp salt bridge, and a series of fatty acid salts with varying charge and hydrocarbon length. Quantitative binding analysis revealed that long-range electrostatic forces and a greasy nonspecific hydrophobic interaction were sufficient for microM potency. The results suggest that an extended interaction site may be necessary for higher potency. We examined a region of the coiled coil immediately C-terminal to the pocket and found that specific salt bridge and hydrogen bond networks may reside in this region. Negatively charged groups extended toward or beyond the C-terminus of the pocket could therefore result in improved low molecular weight fusion inhibitors.