#40 · Structural bio & protein design

Sampling strategy governs which conformational states biomolecular methods recover

The dominant thread is that the sampling procedure, more than the underlying model alone, determines which biomolecular conformations are recovered. In a T4 lysozyme benchmark, generative methods mostly missed buried features when sampling conformational states, as compared against AI-accelerated simulation and enhanced MD. Ensembles from AlphaFold3, AlphaFold2, and RosettaFold were scored against NMR, X-ray, cryo-EM, and MD flexibility profiles, with AF3 performing best. For intrinsically disordered proteins of 15 to 71 residues, OPES multithermal enhanced sampling in a single replica produces atomistic ensembles that reveal transient tertiary structure. What is new is explicit attention to the inference layer as a determinant of results across these studies. The evidence remains preprint-dominated, with only the OPES study published.