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 –> 20150 = 10200 different sequences

Of these ~1038 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 ~ 1/1034 = 0.00000000000000000000000000000001%

Super secondary Structure elements

Structures with alpha-hairpin motifs

beta-hairpinMotifs

beta-alpha-betaMotif

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

folded

unfolded

Sta

bili

ty -G

fold

ing

Sequence

Proteins as “Islands of Stability” in Sequence Space

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Bridges in between islands

Cordes et al. Nat. Struct. Biol 2000 Dec;7(12):1129-32.

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Glykos, N.M., Cesareni, G. & Kokkinidis, M. (1999), Structure 7, 597-603

B1 domain of protein G Janus

< 50% of AAchanged

Paracelsus Challenge