Modularity as an Organizing Principle in Protein Structure

Unequal recombination drives the repetition of structural elements TIM barrel muramidase x 300 Titin

Core of an average domain ~150 AA 20 different amino acids –> = different sequences Of these ~10 38 are expected to have different fold (i.e. less than 20% sequence identity) Estimated number of naturally occurring folds ~1000 Fraction of theoretically possible “folds” used in nature ~ 1/10 34 = %

Super secondary Structure elements

Structures with alpha-hairpin motifs

beta-hairpin Motifs

beta-alpha-beta Motif

Proteins with more than 30% AA identity almost always adopt the same fold.

folded unfolded Stability -  G folding Sequence Proteins as “Islands of Stability” in Sequence Space

Bridges in between islands Cordes et al. Nat. Struct. Biol 2000 Dec;7(12):

Glykos, N.M., Cesareni, G. & Kokkinidis, M. (1999), Structure 7,

B1 domain of protein G Janus < 50% of AA changed Paracelsus Challenge