validation of coevolving residue algorithms via pipeline sensitivity analysis elsc and omes and znmi, oh my!验证通过管道敏感性分析elsc残共同进化算法,和znmi的地步,噢我的天!.pdfVIP

Validation of Coevolving Residue Algorithms via Pipeline Sensitivity Analysis: ELSC and OMES and ZNMI, Oh My! Christopher A. Brown1,2, Kevin S. Brown3,4* 1 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America, 2 FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, United States of America, 3 Department of Physics, University of California Santa Barbara, Santa Barbara, California, United States of America, 4 Institute for Collaborative Biotechnologies, University of California Santa Barbara, Santa Barbara, California, United States of America Abstract Correlated amino acid substitution algorithms attempt to discover groups of residues that co-fluctuate due to either structural or functional constraints. Although these algorithms could inform both ab initio protein folding calculations and evolutionary studies, their utility for these purposes has been hindered by a lack of confidence in their predictions due to hard to control sources of error. To complicate matters further, naive users are confronted with a multitude of methods to choose from, in addition to the mechanics of assembling and pruning a dataset. We first introduce a new pair scoring method, called ZNMI (Z-scored-product Normalized Mutual Information), which drastically improves the performance of mutual information for co-fluctuating residue prediction. Second and more important, we recast the process of finding coevolving residues in proteins as a data-processing pipeline inspired by the medical imaging literature. We construct an ensemble of alignment partitions that can be used in a cross-validation scheme to assess the effects of choices made during the procedure on the resulting predictions. This pipeline sensitivity study gives a measure of reproducibility (how similar are