title: Are residues in a protein folding nucleus evolutionarily conserved?
abstract: Protein is the working molecule of the cell, and evolution is the hallmark of life. It is important to understand how protein folding and evolution influence each other. Several studies correlating experimental measurement of residue participation in folding nucleus and sequence conservation have reached different conclusions. These studies are based on assessment of sequence conservation at folding nucleus sites using entropy or relative entropy measurement derived from multiple sequence alignment. Here we report analysis of conservation of folding nucleus using an evolutionary model alternative to entropy-based approaches. We employ a continuous time Markov model of codon substitution to distinguish mutation fixed by evolution and mutation fixed by chance. This model takes into account bias in codon frequency, bias-favoring transition over transversion, as well as explicit phylogenetic information. We measure selection pressure using the ratio omega of synonymous versus non-synonymous substitution at individual residue site. The omega-values are estimated using the PAML method, a maximum-likelihood estimator. Our results show that there is little correlation between the extent of kinetic participation in protein folding nucleus as measured by experimental phi-value and selection pressure as measured by omega-value. In addition, two randomization tests failed to show that folding nucleus residues are significantly more conserved than the whole protein, or the median omega value of all residues in the protein. These results suggest that at the level of codon substitution, there is no indication that folding nucleus residues are significantly more conserved than other residues. We further reconstruct candidate ancestral residues of the folding nucleus and suggest possible test tube mutation studies for testing folding behavior of ancient folding nucleus.
authors.affiliation: Department of Bioengineering, SEO, MC-063, University of Illinois at Chicago, 851 S. Morgan Street, Room 218, Chicago, IL 60607-7052, USA.
authors.forename: Yan Yuan
authors.initials: YY
authors.lastname: Tseng
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D003062:Codon / Q000235:genetics; D019295:Computational Biology; D017124:Conserved Sequence; D019277:Entropy; D019143:Evolution, Molecular; D007700:Kinetics; D008390:Markov Chains; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012641:Selection, Genetic
chemical_list: D003062:Codon; D011506:Proteins