Energy-intensive single mixed refrigerant (SMR) cycles are employed to produce liquefied natural gas (LNG) at small scale. The energy required for refrigerant compression (shaft work) dominates the overall operating costs of the LNG plant. While current methods to minimize shaft work demand (e.g., exergy analysis) focus on the PRICO cycle, this paper shows that structurally modifying the configuration of SMR cycles can yield significant savings in shaft work demand with low added complexity. The novel SMR cycle developed in this work is based on the CryoMan SMR cycle; its benefits, in terms of energy savings, are demonstrated through a case study for natural gas liquefaction at small scale. The shaft work demand of the PRICO, CryoMan, and novel SMR cycles are minimized using a genetic algorithm and nonlinear optimization. The structural modifications applied tailor the refrigerant composition and exploit complex trade-offs between the operating variables to enhance the energy efficiency of the SMR cycles. The results from the case study demonstrate that the novel SMR cycle achieves 10% savings in shaft work demand in comparison with the PRICO SMR cycle.