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Abstract
Proteins can adopt many distinct conformations, yet the sequence determinants governing which structural states are accessible remain poorly understood. Using fold-switching proteins and AlphaFold as an analytical lens, we identify an organizational principle in which access to alternative structural states-and in some cases the folded state-is governed by surprisingly few amino acids, termed gating residues. Gating generalizes to single-fold proteins, indicating that conformational accessibility is often hierarchically organized around a small number of disproportionately influential residues. AlphaFold has implicitly learned this principle but amplifies and sometimes misapplies it, concentrating conformational control onto too few or incorrect residues. Guided by this principle, targeted MSA editing recovered a conformation AlphaFold confidently mispredicted, suggesting a path toward more accurate prediction of alternative conformations and mutational effects.
