Exploring Protein Sequence Space Using Knowledge-based Potentials

Knowledge-based potentials can be used to decide whether an amino acid sequence is likely to fold into a prescribed native protein structure. We use this idea to survey the sequence–structure relations in protein space. In particular, we test the following two propositions which were found to be important for efficient evolution: the sequences folding into a particular native fold form extensive neutral networks that percolate through sequence space. The neutral networks of any two native folds approach each other to within a few point mutations. Computer simulations using two very different potential functions, M. Sipplʹs PROSA pair potential and a neural network based potential, are used to verify these claims.