The covalent bond is formed after a nucleophilic addition to a Michael acceptor warhead. In general, nucleophilic additions of thiols to Michael acceptors are key bond-forming processes in the burgeoning field of covalent drug design. The addition of thiols to Michael acceptors, which are α,β-unsaturated carbonyls and their derivatives, is typically considered to involve three key steps. First, the thiol is deprotonated to form a reactive thiolate anion. The nucleophilic thiolate then binds to the β-carbon atom (C β ) of the Michael acceptor, giving rise to an anionic enolate intermediate, as shown in Figure . The third step is the protonation of the enolate, which results in the formation of a neutral adduct. The second step in this process is the rate-determining step, and it is therefore crucial to understand the reaction pathways associated with this step. The nucleophilic addition of thiolates to Michael acceptors have been studied previously using computational methods. Studies typically aim to characterize anionic transition states or compare different electronic structure methods to determine the most appropriate method to model biochemical thio-Michael additions. For example, by calculating reaction profiles based on the S-C β distance, Smith et al. showed that range-separated hybrid density-functional approximations were necessary to predict stable gas-phase enolate intermediates, as other common functionals suffer from spurious delocalization errors that stabilize non-covalently bound chargetransfer complexes. While valuable insights into the reaction mechanism can be elucidated from distance-dependent reaction profiles, such as the bond forming and breaking processes, a fuller understanding of the overall reaction profile requires consideration of molecular conformations.