Summary
Protein Structure prediction methods from both AlphaFold2- and AF3-generation undersample the conformational space that they find to be high-confidence (1). In other words, they will favorably score physiologically relevant conformations when presented indirectly with the structure, but will fail to sample it by default unless hacked with custom alignments and/or templates (e.g., for conformational changes).
1.
Roney JP, Ou C, Ovchinnikov S. Protein Diffusion Models as Statistical Potentials. openRxiv; 2025. Available from: https://doi.org/10.64898/2025.12.09.693073