醛缩酶A
活动站点
突变
分子动力学
酶
化学
人口
定向进化
立体化学
构象集合
生物物理学
突变体
生物化学
计算化学
生物
基因
人口学
社会学
作者
Adrian Romero‐Rivera,Marc Garcia‐Borràs,Sílvia Osuna
标识
DOI:10.1021/acscatal.7b02954
摘要
Enzymes exist as ensembles of conformations that are important for function. Tuning these populations of conformational states through mutation enables evolution toward additional activities. Here we computationally evaluate the population shifts induced by distal and active site mutations in a family of computationally designed and experimentally optimized retro-aldolases. The conformational landscape of these enzymes was significantly altered during evolution, as pre-existing catalytically active conformational substates became major states in the most evolved variants. We further demonstrate that key residues responsible for these substate conversions can be predicted computationally. Significantly, the identified residues coincide with those positions mutated in the laboratory evolution experiments. This study establishes that distal mutations that affect enzyme catalytic activity can be predicted computationally and thus provides the enzyme (re)design field with a rational strategy to determine promising sites for enhancing activity through mutation.
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