SubTuner leverages physics-based modeling to complement AI in enzyme engineering toward non-native substrates

IF 11.5 Q1 CHEMISTRY, PHYSICAL
Qianzhen Shao, Asher C. Hollenbeak, Yaoyukun Jiang, Xinchun Ran, Brian O. Bachmann, Zhongyue J. Yang
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引用次数: 0

Abstract

We developed SubTuner, a physics-based computational tool that tackles the challenge of identifying enzyme mutants with enhanced activity for specified non-native substrates. To test the performance of SubTuner, we designed three tasks, all aiming to identify beneficial anion methyltransferase mutants for synthesis of non-native S-adenosyl-L-methionine analogs: first, in the conversion of ethyl iodide from a pool of 190 Arabidopsis thaliana Harmless to Ozone Layer 1 (AtHOL1) single-point mutants for an initial test of accuracy and speed; second, of ethyl, n-propyl, cyclopropylmethyl, and phenethyl iodides from a pool of 600 Aspergillus clavatus methyltransferase multi-point mutants for a test of generalizability; and, eventually, of bulkier substrates for AtHOL1 combined with experimental characterization for a test of a priori predictivity. All tests demonstrated SubTuner’s ability to accelerate enzyme engineering for non-native substrates, superior to existing bioinformatics and machine-learning-based tools. SubTuner, with its physical hypothesis, quantitative accuracy, and mechanism-informing ability, holds significant potential to aid enzyme engineering for substrate scope expansion.

Abstract Image

SubTuner利用基于物理的建模来补充AI在酶工程对非天然底物
我们开发了SubTuner,这是一种基于物理的计算工具,可以解决识别对特定非天然底物具有增强活性的酶突变体的挑战。为了测试SubTuner的性能,我们设计了三个任务,目的都是为了鉴定对合成非天然s -腺苷- l-蛋氨酸类似物有益的阴离子甲基转移酶突变体:首先,从190个对臭氧层1无害的拟南芥(AtHOL1)单点突变体中转化碘乙基,以进行准确性和速度的初步测试;第二,从600个棒曲霉甲基转移酶多点突变体中提取乙基、正丙基、环丙基甲基和苯乙基碘化物,进行普遍性测试;最终,将体积更大的AtHOL1底物与实验表征相结合,用于先验预测性的测试。所有测试都表明,SubTuner能够加速非天然底物的酶工程,优于现有的生物信息学和基于机器学习的工具。SubTuner凭借其物理假设、定量准确性和机制信息能力,在帮助酶工程扩大底物范围方面具有重大潜力。
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来源期刊
CiteScore
10.50
自引率
6.40%
发文量
0
期刊介绍: Chem Catalysis is a monthly journal that publishes innovative research on fundamental and applied catalysis, providing a platform for researchers across chemistry, chemical engineering, and related fields. It serves as a premier resource for scientists and engineers in academia and industry, covering heterogeneous, homogeneous, and biocatalysis. Emphasizing transformative methods and technologies, the journal aims to advance understanding, introduce novel catalysts, and connect fundamental insights to real-world applications for societal benefit.
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