Design of noncovalent irreversible complexes with fast assembly rates. The realization that the selfassembly initiation by the exterior intermolecular interaction and the control of the complexation time largely by the priming time explains why the presence of a cryptic exterior site for substrate or inhibitor binding at the rim of the enzyme active site is a fundamental feature of fast enzymes such as acetylcholinesterase and why it is advantageous for the proapoptotic multidomain BAK protein to have a noncanonical BH3-binding groove that abuts the canonical one for constrictive complexation of BAK-due to the steric hindrance from R88 and Y89 on the edge of the canonical groove -with proapoptotic BH3-only proteins. The realization that the self-assembly acceleration by the adoption of populated conformations for the exterior intermolecular interaction also explains why small molecules reportedly prefer to adopt local minimum conformations when binding to proteins .