title: Coarse-grained sequences for protein folding and design.
abstract: We present the results of sequence design on our off-lattice minimalist model in which no specification of native-state tertiary contacts is needed. We start with a sequence that adopts a target topology and build on it through sequence mutation to produce new sequences that comprise distinct members within a target fold class. In this work, we use the alpha/beta ubiquitin fold class and design two new sequences that, when characterized through folding simulations, reproduce the differences in folding mechanism seen experimentally for proteins L and G. The primary implication of this work is that patterning of hydrophobic and hydrophilic residues is the physical origin for the success of relative contact-order descriptions of folding, and that these physics-based potentials provide a predictive connection between free energy landscapes and amino acid sequence (the original protein folding problem). We present results of the sequence mapping from a 20- to the three-letter code for determining a sequence that folds into the WW domain topology to illustrate future extensions to protein design.
authors.affiliation: Department of Bioengineering, University of California, Berkeley, CA 94720, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Brown
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Fawzi
authors.forename: Teresa
authors.initials: T
authors.lastname: Head-Gordon
mesh_terms: D000595:Amino Acid Sequence; D007700:Kinetics; D008956:Models, Chemical; D008969:Molecular Sequence Data; D017510:Protein Folding; D017386:Sequence Homology, Amino Acid