Co‐evolutionary constraints of globular proteins correlate with their folding rates

Folding rates (ln k f ) of globular proteins correlate with their biophysical properties, but relationship between ln k f and patterns of sequence evolution remains elusive. We introduce ‘relative co‐evolution order’ ( rCEO ) as length‐normalized average primary chain separation of co‐evolving pairs (CEPs), which negatively correlates with ln k f . In addition to pairs in native 3D contact, indirectly connected and structurally remote CEPs probably also play critical roles in protein folding. Correlation between rCEO and ln k f is stronger in multi‐state proteins than two‐state proteins, contrasting the case of contact order ( co ), where stronger correlation is found in two‐state proteins. Finally, rCEO , co and ln k f are fitted into a 3D linear correlation.