Coiled coils are bundles of two or more α-helices that wrap around each other to form superhelical complexes. Coiled coils can adopt a variety of parallel, antiparallel or mixed (e.g. up-down-up) topologies, which can be characterised with three geometric descriptors: the coiled coil radius, interface (Crick) angle and pitch (Figure ). The assemblies possess a distinctive type of packing termed knobs-into-holes (KIH), where a side chain from one helix ('knob') packs into a diamond-shaped cavity ('hole') formed by four side chains in a different helix of the bundle. This distinguishes coiled coils from other helical bundles, which are characterised by less intimate packing. This packing arrangement is supported by sequence repeats of hydrophobic (h) and polar (p) residues, usually in heptad repeats hpphppp, often denoted in the form of an abcdefg register. In these heptad repeats, the hydrophobic residues have an average spacing of 3.5 residues, giving rise to amphipathic helices, composed of a hydrophobic and a hydrophilic face. Since there is a small spacing deviation between 3.5 in heptad repeats and 3.6 in ideal α-helices, the hydrophobic face of a helix with 3.5 spacing proceeds around the helix, leading to supercoiling of helices upon assembly rather than packing in a straight manner. Coiled-coil assembly is driven by the hydrophobic effect, where the helices assemble to bury their hydrophobic faces in a hydrophobic core. The nature of the hydrophobic residues at the a and d positions of the heptad repeat largely determines the oligomerisation state of coiled-coil dimers, trimers and tetramers. Further helices can be recruited to the assembly via the expansion of the hydrophobic interface, achieved by introducing hydrophobic residues at the e and g positions. The wealth of knowledge about these topological arrangements have contributed to turn-blies, these methods frequently produce binding free estimates with large statistical errors and make a number of approximations, such as neglecting or partially accounting for the effects of changes in internal energy and entropy on protein association free energies, resulting in limited accuracy. More rigorous free energy methods such as alchemical binding free energy calculations have become established for the computation of binding free energies of small molecules to proteins with MD. Whilst in theory an alchemical pathway could be constructed via decoupling a binding partner in a protein-protein complex from its environment in the bound and unbound states, the alchemical decoupling of a complete protein molecule will usually result in poor convergence due to large free energy changes. This is expected to be particularly problematic for coiled coils, given the magnitude of electrostatic interactions present due to their multiple charged residues.