標題: Systems-level Modeling with Molecular Resolution Elucidates the Rate-limiting Mechanisms of Cellulose Decomposition by Cellobiohydrolases
作者: Shang, Barry Z.
Chang, Rakwoo
Chu, Jhih-Wei
生物科技學系
生物資訊及系統生物研究所
Department of Biological Science and Technology
Institude of Bioinformatics and Systems Biology
關鍵字: Cellulase;Computational Biology;Enzyme Inactivation;Enzyme Kinetics;Macromolecular Crowding;Molecular Modeling;Systems Biology;Interfacial Biocatalysis;Spatiotemporal Modeling
公開日期: 4-十月-2013
摘要: Interprotein and enzyme-substrate couplings in interfacial biocatalysis induce spatial correlations beyond the capabilities of classical mass-action principles in modeling reaction kinetics. To understand the impact of spatial constraints on enzyme kinetics, we developed a computational scheme to simulate the reaction network of enzymes with the structures of individual proteins and substrate molecules explicitly resolved in the three-dimensional space. This methodology was applied to elucidate the rate-limiting mechanisms of crystalline cellulose decomposition by cellobiohydrolases. We illustrate that the primary bottlenecks are slow complexation of glucan chains into the enzyme active site and excessive enzyme jamming along the crowded substrate. Jamming could be alleviated by increasing the decomplexation rate constant but at the expense of reduced processivity. We demonstrate that enhancing the apparent reaction rate required a subtle balance between accelerating the complexation driving force and simultaneously avoiding enzyme jamming. Via a spatiotemporal systems analysis, we developed a unified mechanistic framework that delineates the experimental conditions under which different sets of rate-limiting behaviors emerge. We found that optimization of the complexation-exchange kinetics is critical for overcoming the barriers imposed by interfacial confinement and accelerating the apparent rate of enzymatic cellulose decomposition.
URI: http://dx.doi.org/10.1074/jbc.M113.497412
http://hdl.handle.net/11536/23664
ISSN: 0021-9258
DOI: 10.1074/jbc.M113.497412
期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
Volume: 288
Issue: 40
起始頁: 29081
結束頁: 29089
顯示於類別:期刊論文


文件中的檔案:

  1. 000330298800061.pdf