X-ray crystallography studies have identified that most cyclic inhibitors of HIV protease (including cyclic ureas) bind in a symmetric manner, however some cyclic inhibitors, such as cyclic sulfamides, bind in a non-symmetric manner. This raises the question as to whether it is possible for cyclic sulfamides to bind symmetrically and conversely for cyclic ureas to bind non-symmetrically. Herein we report an analysis of the conformational preference of cyclic ureas and sulfamides both free in solution and bound to HIV protease, including an investigation of the effect of branching. Quantum chemical calculations (B3LYP, M06-2X, MP2, CCSD(T)) predict the cyclic urea to prefer a symmetric conformation in solution, with a large activation barrier towards inter-conversion to the non-symmetric conformation. This differs from the cyclic sulfamides, which marginally prefer a non-symmetric conformation with a much smaller barrier to inter-conversion making it more likely for a non-preferred conformation to be observed. It is predicted that the cyclic scaffold itself favours a symmetric form, while branching induces a preference for a non-symmetric form. MD simulations on the free inhibitors identified inter-conversion with the cyclic sulfamides but not the cyclic ureas, in support of the quantum chemical results. MM-PB(GB)SA calculations on the cyclic inhibitors bound to HIV protease corroborate the X-ray crystallography studies, identifying the cyclic ureas to bind symmetrically and the cyclic sulfamides in a non-symmetrical manner. While the non-preferred form of the sulfamide may well be present as a free molecule in solution, our results suggest that it is unlikely to bind to HIV protease in a symmetric manner.