assessing the accuracy of ancestral protein reconstruction methods评估的准确性祖先蛋白质重建方法.pdf

Assessing the Accuracy of Ancestral Protein Reconstruction Methods 1 2 3 3* Paul D. Williams , David D. Pollock , Benjamin P. Blackburne , Richard A. Goldstein 1 Department of Chemistry, University of Michigan, Ann Arbor, Michigan, United States of America, 2 Department of Biological Sciences, Biological Computation and Visualization Center, Louisiana State University, Baton Rouge, Louisiana, United States of America, 3 Division of Mathematical Biology, National Institute of Medical Research, Mill Hill, London, United Kingdom The phylogenetic inference of ancestral protein sequences is a powerful technique for the study of molecular evolution, but any conclusions drawn from such studies are only as good as the accuracy of the reconstruction method. Every inference method leads to errors in the ancestral protein sequence, resulting in potentially misleading estimates of the ancestral protein’s properties. To assess the accuracy of ancestral protein reconstruction methods, we performed computational population evolution simulations featuring near-neutral evolution under purifying selection, speciation, and divergence using an off-lattice protein model where fitness depends on the ability to be stable in a specified target structure. We were thus able to compare the thermodynamic properties of the true ancestral sequences with the properties of ‘‘ancestral sequences’’ inferred by maximum parsimony, maximum likelihood, and Bayesian methods. Surprisingly, we found that methods such as maximum parsimony and maximum likelihood that reconstruct a ‘‘best guess’’ amino acid at each position overestimate thermostability, while a Bayesian method that sometimes chooses less-probable residues from the posterior probability distribution