Ke WU1,2, Jiahao LUO1,2, Feiran LI1,2
Received:
2024-12-02
Revised:
2025-02-12
Published:
2025-02-14
Contact:
Feiran LI
吴柯1,2, 罗家豪1,2, 李斐然1,2
通讯作者:
李斐然
作者简介:
基金资助:
CLC Number:
Ke WU, Jiahao LUO, Feiran LI. Machine Learning Applications in Genome-scale Metabolic Model Reconstruction and Curation[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2024-090.
吴柯, 罗家豪, 李斐然. 机器学习驱动的基因组规模代谢模型构建与优化[J]. 合成生物学, DOI: 10.12211/2096-8280.2024-090.
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URL: https://synbioj.cip.com.cn/EN/10.12211/2096-8280.2024-090
模型应用 | 方法 | 模型框架 | 输入 | 输出 | 特点 |
---|---|---|---|---|---|
辅助 基因注释 | DeepEC[ | CNN | 氨基酸序列 | EC编号 | 可区分酶与非酶,无法进行多功能注释 |
CLEAN[ | 预训练蛋白质大语言模型(ESM-1b),对比学习 | 氨基酸序列 | EC编号 | 无法区分酶与非酶,可进行多功能注释,可用于数据极少的EC编号 | |
DeepECtransformer[ | 预训练蛋白质大语言模型(ProtBert),Transformer | 氨基酸序列 | EC编号 | 可区分酶与非酶,可进行多功能注释,不可用于数据极少的EC编号 | |
ECRECer[ | 预训练蛋白质大语言模型(ESM-1b) ,GRU | 氨基酸序列 | EC编号 | 可区分酶与非酶,可进行多功能注释 | |
ECPICK[ | One-hot,CNN | 氨基酸序列 | EC编号 | 无法区分酶与非酶,不可进行多功能注释,可输出预测EC编号的置信度 | |
EnzBert[ | Transformer | 氨基酸序列 | EC编号 | 无法区分酶与非酶,不可进行多功能注释,可推测关键残基 | |
EnzymeNet[ | CNN,ResNet | 氨基酸序列 | EC编号 | 可区分酶与非酶,无法进行多功能注释 | |
GraphEC[ | 预训练蛋白质大语言模型(ProtTrans),ESMFold | 氨基酸序列和蛋白质三维结构 | EC编号 | 无法区分酶与非酶,可进行多功能注释,计算资源需求高 | |
辅助途径解析-反应预测 | RetroPath RL[ | 基于蒙特卡洛树搜索的 强化学习方法 | 化合物 SMILES | 合成途径 | 缓解组合爆炸问题,允许探索深度是只基于模板版本的两倍以上 |
ASKCOS[ | FNN | 化合物 SMILES | 合成途径 | 缓解组合爆炸问题,适用于化学合成途径设计 | |
chemoenzymatic- ASKCOS[ | DNN | 化合物 SMILES | 合成途径 | 缓解组合爆炸问题,可进行化学合成与生物合成混合途径设计 | |
RetroBioCat[ | DNN | 化合物 SMILES | 合成途径 | 缓解组合爆炸问题, 处理大分子化合物存在挑战 | |
Kreutter et al[ | Transformer | 化合物 SMILES和酶功能描述 | 反应产物 | 预测单步反应,无法给出完整的反应,无法推荐酶功能 | |
Probst et al[ | Transformer | 化合物 SMILES和EC编号 | 反应产物 | 预测单步反应,无法给出完整的反应,无法推荐EC编号 | |
BioNavi-NP[ | Transformer | 天然产品的SMILES | 合成途径 | 针对天然产物及类似物,可预测多步途径 | |
BioNavi[ | Transformer | 化合物 SMILES | 合成途径 | 可进行化学合成与生物合成混合途径设计 | |
辅助 途径解析-酶挖掘 | ESP[ | 预训练蛋白质大语言模型(ESM-1b),GNN,XGBoost | 氨基酸序列和分子指纹 | 酶-底物结合 可能性 | 对于训练集中没出现代谢物的预测性能会有明显下降 |
EnzRank[ | 分子指纹,CNN | 氨基酸序列和分子指纹 | 酶-底物结合 可能性 | 对于天然底物及其相似物具有良好的区分能力 | |
PU-EPP[ | GNN,正样本和无标签学习 | 氨基酸序列和化合物SMILES | 酶-底物结合 可能性 | 鲁棒性强,可鉴定酶和底物的关键位点 | |
MEI | 预训练蛋白质大语言模型 (ESM-1b),GNN,DNN | 氨基酸序列和化合物SMILES | 酶-底物结合 可能性 | 可利用专业数据集微调进行特定任务预测 | |
REME[ | 集成ESP、DLKcat/TurNuP、DeepET等模型 | 反应SMILES | 酶列表 | 多维度评价与筛选有效提高了推荐酶列表的可信度 | |
SPEPP[ | Word2Vec,Transformer | 底物、反应物和酶 | 酶催化底物- 产物反应的 可能性 | 计算效率相较基于相似性的方法显著提高,可大规模使用,需要提供候选酶集合 | |
辅助空缺填补 | BoostGAPFILL[ | 基于矩阵分解的 推荐系统技术 | 代谢模型 | 填补反应 | 融合了拓扑和约束方法,能够识别代谢网络中的潜在模式 |
CHESHIRE[ | GCN | 代谢模型 | 填补反应 | 计算效率高,可解释性强,可能引入假阳性反应,缺少反应方向性信息 | |
DSHCNet[ | GCN,MLP | 代谢模型 | 填补反应 | 对反应数据依赖较强,在适应不同反应数据库中存在挑战 | |
DNNGIOR[ | CNN | 代谢模型 | 填补反应 | 预测性能受系统发育距离影响 |
Table 1 Machine learning methods for assisting the expansion of GEM
模型应用 | 方法 | 模型框架 | 输入 | 输出 | 特点 |
---|---|---|---|---|---|
辅助 基因注释 | DeepEC[ | CNN | 氨基酸序列 | EC编号 | 可区分酶与非酶,无法进行多功能注释 |
CLEAN[ | 预训练蛋白质大语言模型(ESM-1b),对比学习 | 氨基酸序列 | EC编号 | 无法区分酶与非酶,可进行多功能注释,可用于数据极少的EC编号 | |
DeepECtransformer[ | 预训练蛋白质大语言模型(ProtBert),Transformer | 氨基酸序列 | EC编号 | 可区分酶与非酶,可进行多功能注释,不可用于数据极少的EC编号 | |
ECRECer[ | 预训练蛋白质大语言模型(ESM-1b) ,GRU | 氨基酸序列 | EC编号 | 可区分酶与非酶,可进行多功能注释 | |
ECPICK[ | One-hot,CNN | 氨基酸序列 | EC编号 | 无法区分酶与非酶,不可进行多功能注释,可输出预测EC编号的置信度 | |
EnzBert[ | Transformer | 氨基酸序列 | EC编号 | 无法区分酶与非酶,不可进行多功能注释,可推测关键残基 | |
EnzymeNet[ | CNN,ResNet | 氨基酸序列 | EC编号 | 可区分酶与非酶,无法进行多功能注释 | |
GraphEC[ | 预训练蛋白质大语言模型(ProtTrans),ESMFold | 氨基酸序列和蛋白质三维结构 | EC编号 | 无法区分酶与非酶,可进行多功能注释,计算资源需求高 | |
辅助途径解析-反应预测 | RetroPath RL[ | 基于蒙特卡洛树搜索的 强化学习方法 | 化合物 SMILES | 合成途径 | 缓解组合爆炸问题,允许探索深度是只基于模板版本的两倍以上 |
ASKCOS[ | FNN | 化合物 SMILES | 合成途径 | 缓解组合爆炸问题,适用于化学合成途径设计 | |
chemoenzymatic- ASKCOS[ | DNN | 化合物 SMILES | 合成途径 | 缓解组合爆炸问题,可进行化学合成与生物合成混合途径设计 | |
RetroBioCat[ | DNN | 化合物 SMILES | 合成途径 | 缓解组合爆炸问题, 处理大分子化合物存在挑战 | |
Kreutter et al[ | Transformer | 化合物 SMILES和酶功能描述 | 反应产物 | 预测单步反应,无法给出完整的反应,无法推荐酶功能 | |
Probst et al[ | Transformer | 化合物 SMILES和EC编号 | 反应产物 | 预测单步反应,无法给出完整的反应,无法推荐EC编号 | |
BioNavi-NP[ | Transformer | 天然产品的SMILES | 合成途径 | 针对天然产物及类似物,可预测多步途径 | |
BioNavi[ | Transformer | 化合物 SMILES | 合成途径 | 可进行化学合成与生物合成混合途径设计 | |
辅助 途径解析-酶挖掘 | ESP[ | 预训练蛋白质大语言模型(ESM-1b),GNN,XGBoost | 氨基酸序列和分子指纹 | 酶-底物结合 可能性 | 对于训练集中没出现代谢物的预测性能会有明显下降 |
EnzRank[ | 分子指纹,CNN | 氨基酸序列和分子指纹 | 酶-底物结合 可能性 | 对于天然底物及其相似物具有良好的区分能力 | |
PU-EPP[ | GNN,正样本和无标签学习 | 氨基酸序列和化合物SMILES | 酶-底物结合 可能性 | 鲁棒性强,可鉴定酶和底物的关键位点 | |
MEI | 预训练蛋白质大语言模型 (ESM-1b),GNN,DNN | 氨基酸序列和化合物SMILES | 酶-底物结合 可能性 | 可利用专业数据集微调进行特定任务预测 | |
REME[ | 集成ESP、DLKcat/TurNuP、DeepET等模型 | 反应SMILES | 酶列表 | 多维度评价与筛选有效提高了推荐酶列表的可信度 | |
SPEPP[ | Word2Vec,Transformer | 底物、反应物和酶 | 酶催化底物- 产物反应的 可能性 | 计算效率相较基于相似性的方法显著提高,可大规模使用,需要提供候选酶集合 | |
辅助空缺填补 | BoostGAPFILL[ | 基于矩阵分解的 推荐系统技术 | 代谢模型 | 填补反应 | 融合了拓扑和约束方法,能够识别代谢网络中的潜在模式 |
CHESHIRE[ | GCN | 代谢模型 | 填补反应 | 计算效率高,可解释性强,可能引入假阳性反应,缺少反应方向性信息 | |
DSHCNet[ | GCN,MLP | 代谢模型 | 填补反应 | 对反应数据依赖较强,在适应不同反应数据库中存在挑战 | |
DNNGIOR[ | CNN | 代谢模型 | 填补反应 | 预测性能受系统发育距离影响 |
参数类型 | 方法 | 模型框架 | 输入 | 输出 | 特点 |
---|---|---|---|---|---|
动力学参数 | Heckmann et al[ | 随机森林,MLP | GEM/蛋白质结构/EC号首位/pH等 | kcat | 可预测体内kcat,适用于大肠杆菌 |
DLKcat[ | GNN,CNN | 氨基酸序列和 化合物SMILES | kcat | 预测kcat(R2=0.44),内置于GECKO 3.0 | |
TurNuP [ | 预训练蛋白质大语言模型(ESM-1b),XGBoost | 氨基酸序列和 反应指纹 | kcat | 预测kcat(R2=0.44),无法区分多底物反应中不同底物的kcat | |
DLTKcat [ | GNN,CNN | 氨基酸序列,化合物SMILES和温度 | kcat | 预测不同温度下的kcat(R2=0.66) | |
DeepEnzyme [ | GCN | 氨基酸序列,化合物SMILES和蛋白质三维结构 | kcat | 预测kcat(R2=0.58),预测突变型需要具备蛋白质结构预测能力 | |
Kroll et al [ | 预训练蛋白质大语言模型(ESM-1b) | 氨基酸序列和分子指纹 | Km | 预测Km(R2=0.53) | |
GraphKM [ | 预训练蛋白质大语言模型(ESM-2),GNN | 氨基酸序列和化合物SMILES | Km | 预测Km(R2=0.62),模型的预测性能受限于训练数据集的规模和质量 | |
MLAGO [ | 随机森林 | EC 编号, KEGG ID和物种编号 | Km | 预测Km(R2=0.53),泛化能力受限于EC 编号, KEGG ID, 物种编号信息 | |
MPEK [ | 预训练蛋白质大语言模型(ProtT5),预训练小分子大语言模型(Mole-BERT),多任务学习 | 氨基酸序列和化合物SMILES | kcat和Km | 支持同时预测kcat(R2=0.64)和Km(R2=0.60) | |
UniKP [ | 预训练蛋白质大语言模型(UniRef50),预训练小分子大语言模型(SMILES Transformer),极度随机树 | 氨基酸序列和化合物SMILES | kcat、Km和kcat/ Km | 支持分别预测kcat(R2=0.67)、 Km(R2=0.60)和 kcat/Km(R2=0.56),鲁棒性强,支持温度和pH 输入 | |
EITLEM- Kinetics [ | 预训练蛋白质大语言模型(ESM-1v),迁移学习 | 氨基酸序列和化合物SMILES | kcat、Km和kcat/Km | 支持分别kcat(R2=0.72),Km(R2=0.69)和 kcat/Km(R2=0.68)预测,蛋白突变体的kcat预测性能优异 | |
热力学参数 | dGPredictor[ | 线性回归模型 | 分子指纹 | ΔrG′o | 不适用于异构化反应与涉及金属或聚合物结构的反应 |
Alazmi et al[ | 线性回归模型 | 分子指纹 | ΔrG′ o | 特征提取方式通用性强,可用于非4天然反应 | |
温度相关 参数 | DeepSTABp [ | 预训练蛋白质大语言模型(ProtTrans),MLP | 氨基酸序列、生物体生长温度和实验条件 | Tm | 预测能力对点突变不敏感 |
DeepTM [ | GCN | 氨基酸序列 | Tm | 特征提取复杂,训练数据未考虑其它对蛋白熔解温度影响的因素 | |
Tome[ | SVR,随机森林 | 氨基酸序列,OGT | Topt | 训练集高于85°C的Topt值占比不足5%,限制了Tome对高温稳定性酶的预测能力 | |
TOMER[ | 集成学习 | 氨基酸序列,OGT | Topt | 重采样缓解了数据分布不平衡,对高于85°C的Topt 值预测性能显著提升 | |
DeepET[ | ResNet,迁移学习 | 氨基酸序列 | Tm 和Topt | 类似于Tome,数据分布不均衡会限制其对极端温度蛋白质的预测性能 | |
Preoptem[ | One-hot,CNN | 氨基酸序列 | Topt | Pearson 相关系数 r=0.58,适用于嗜热蛋白 |
Table 2 Machine learning methods for assisting obtaining parameters of multi-constraint and multi-process model
参数类型 | 方法 | 模型框架 | 输入 | 输出 | 特点 |
---|---|---|---|---|---|
动力学参数 | Heckmann et al[ | 随机森林,MLP | GEM/蛋白质结构/EC号首位/pH等 | kcat | 可预测体内kcat,适用于大肠杆菌 |
DLKcat[ | GNN,CNN | 氨基酸序列和 化合物SMILES | kcat | 预测kcat(R2=0.44),内置于GECKO 3.0 | |
TurNuP [ | 预训练蛋白质大语言模型(ESM-1b),XGBoost | 氨基酸序列和 反应指纹 | kcat | 预测kcat(R2=0.44),无法区分多底物反应中不同底物的kcat | |
DLTKcat [ | GNN,CNN | 氨基酸序列,化合物SMILES和温度 | kcat | 预测不同温度下的kcat(R2=0.66) | |
DeepEnzyme [ | GCN | 氨基酸序列,化合物SMILES和蛋白质三维结构 | kcat | 预测kcat(R2=0.58),预测突变型需要具备蛋白质结构预测能力 | |
Kroll et al [ | 预训练蛋白质大语言模型(ESM-1b) | 氨基酸序列和分子指纹 | Km | 预测Km(R2=0.53) | |
GraphKM [ | 预训练蛋白质大语言模型(ESM-2),GNN | 氨基酸序列和化合物SMILES | Km | 预测Km(R2=0.62),模型的预测性能受限于训练数据集的规模和质量 | |
MLAGO [ | 随机森林 | EC 编号, KEGG ID和物种编号 | Km | 预测Km(R2=0.53),泛化能力受限于EC 编号, KEGG ID, 物种编号信息 | |
MPEK [ | 预训练蛋白质大语言模型(ProtT5),预训练小分子大语言模型(Mole-BERT),多任务学习 | 氨基酸序列和化合物SMILES | kcat和Km | 支持同时预测kcat(R2=0.64)和Km(R2=0.60) | |
UniKP [ | 预训练蛋白质大语言模型(UniRef50),预训练小分子大语言模型(SMILES Transformer),极度随机树 | 氨基酸序列和化合物SMILES | kcat、Km和kcat/ Km | 支持分别预测kcat(R2=0.67)、 Km(R2=0.60)和 kcat/Km(R2=0.56),鲁棒性强,支持温度和pH 输入 | |
EITLEM- Kinetics [ | 预训练蛋白质大语言模型(ESM-1v),迁移学习 | 氨基酸序列和化合物SMILES | kcat、Km和kcat/Km | 支持分别kcat(R2=0.72),Km(R2=0.69)和 kcat/Km(R2=0.68)预测,蛋白突变体的kcat预测性能优异 | |
热力学参数 | dGPredictor[ | 线性回归模型 | 分子指纹 | ΔrG′o | 不适用于异构化反应与涉及金属或聚合物结构的反应 |
Alazmi et al[ | 线性回归模型 | 分子指纹 | ΔrG′ o | 特征提取方式通用性强,可用于非4天然反应 | |
温度相关 参数 | DeepSTABp [ | 预训练蛋白质大语言模型(ProtTrans),MLP | 氨基酸序列、生物体生长温度和实验条件 | Tm | 预测能力对点突变不敏感 |
DeepTM [ | GCN | 氨基酸序列 | Tm | 特征提取复杂,训练数据未考虑其它对蛋白熔解温度影响的因素 | |
Tome[ | SVR,随机森林 | 氨基酸序列,OGT | Topt | 训练集高于85°C的Topt值占比不足5%,限制了Tome对高温稳定性酶的预测能力 | |
TOMER[ | 集成学习 | 氨基酸序列,OGT | Topt | 重采样缓解了数据分布不平衡,对高于85°C的Topt 值预测性能显著提升 | |
DeepET[ | ResNet,迁移学习 | 氨基酸序列 | Tm 和Topt | 类似于Tome,数据分布不均衡会限制其对极端温度蛋白质的预测性能 | |
Preoptem[ | One-hot,CNN | 氨基酸序列 | Topt | Pearson 相关系数 r=0.58,适用于嗜热蛋白 |
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