The energy difference can be calculated from single, lowest lying conformers for each diastereomeric TS identified using a conformational search algorithm. Alternatively, multiple thermally accessible conformations, and their Boltzmann population distribution, can be used to obtain the energy difference. In both cases, the challenge of TS structure-based approaches is to identify and optimize all potential diastereomeric TSs of the reaction under investigation. In practice, the simplicity of the Curtin-Hammet principle is overshadowed by the number of possible TS conformations, or reactions for which multiple steps could be rate-determining, or for which multiple competing mechanisms leading to opposite enantiomeric products exist. For these methods to be user-friendly, an automated conformational search algorithm is needed. Automated conformational sampling of TSs lies at the heart of tools like VIRTUAL CHEMIST/ACE, CatVS/Q2MM, QChASM/AARON (Quantum Chemistry Automation and Structure Manipulation/An Automated Reaction Optimizer for New catalysts), or the chemical steering wheel. VIRTUAL CHEMIST/ACE, developed in our research group, is a self-contained, graphics user interface (GUI)-based asymmetric catalyst design platform. Designed with a chemist's needs in mind, the underlying MM methodology has been thoroughly tested on seven widespread metal and organocatalyzed reactions, with an overall accuracy of ~ 1 kcal/mol (Box 3). To note, VIRTUAL CHEMIST was also applied to several scenarios that an experimental chemist might face in his project: one-by-one catalyst design, screening a library of catalysts, catalyst lead optimization through analogue search (detailed in the Evaluation of the Models, Methods, and Applications section), and identifying the substrate scope of a known catalyst, with demonstrated advantages over traditional asymmetric catalyst design.