The efficacy of calixarenes-for the storage and/or detection of small guest molecules at the upper-rim is well-known. As part of our continuing efforts to investigate the ability to fine-tune the structure and hence host-guest binding characteristics of calixarenes, we present a systematic investigation of the effect of methylation of the lower-rim tetraphenolic pocket of calix[4]arene (C[4]) on binding at the upper-rim for a test-suite of guest molecules consisting of H-2, O-2, N-2, H2O, CO2, NH3, H2S, N2O, HCN, and SO2. Results of the effects on the host-guest binding for all permutations of single, double, triple and quadruple methylations are presented. It was found that while a tetraphenolic C[4] host does not discriminate between many of the guest molecules in terms of binding energies, progressively methylated lower-rim C[4] hosts introduce differences in guest binding energies within the upper cavity to the extent where it may be possible to competitively bind one guest over another over a wide range of guests. In this regard, this family of methylated C[4] hosts show promise as gas separation devices.