A Phylogenetic Analysis of Normal Modes Evolution in Enzymes and Its Relationship to Enzyme Function

JOURNAL OF MOLECULAR BIOLOGY

卷:422

Article

Lai, Jason²  Jin, Jing^1,3  Kubelka, Jan¹  Liberles, David A.² 

[1] Univ Wyoming, Dept Chem, Laramie, WY 82071 USA

[2] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA

[3] Goshen Coll, Program Biochem & Mol Biol, Goshen, IN 46526 USA

关键词: sequence-structure-function relationship;    molecular evolution;    bioinformaticsprotein dynamics;    enzyme function;    normal mode analysis;   

DOI  :  10.1016/j.jmb.2012.05.028

来源: Elsevier

【 摘 要 】

Since the dynamic nature of protein structures is essential for enzymatic function, it is expected that functional evolution can be inferred from the changes in protein dynamics. However, dynamics can also diverge neutrally with sequence substitution between enzymes without changes of function. In this study, a phylogenetic approach is implemented to explore the relationship between enzyme dynamics and function through evolutionary history. Protein dynamics are described by normal mode analysis based on a simplified harmonic potential force field applied to the reduced C-alpha representation of the protein structure while enzymatic function is described by Enzyme Commission numbers. Similarity of the binding pocket dynamics at each branch of the protein family's phylogeny was analyzed in two ways: (1) explicitly by quantifying the normal mode overlap calculated for the reconstructed ancestral proteins at each end and (2) implicitly using a diffusion model to obtain the reconstructed lineage-specific changes in the normal modes. Both explicit and implicit ancestral reconstruction identified generally faster rates of change in dynamics compared with the expected change from neutral evolution at the branches of potential functional divergences for the alpha-amylase, D-isomer-specific 2-hydroxyacid dehydrogenase, and copper-containing amine oxidase protein families. Normal mode analysis added additional information over just comparing the RMSD of static structures. However, the branchspecific changes were not statistically significant compared to background function-independent neutral rates of change of dynamic properties and blind application of the analysis would not enable prediction of changes in enzyme specificity. (c) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free