人工智能蛋白质结构设计算法研究进展

doi:10.12211/2096-8280.2023-008

摘要/Abstract

摘要：

蛋白质是各类生命活动不可缺少的承担者，其序列决定了折叠后的三维结构和功能。这些具有特定功能的蛋白质在生物医学等多个领域具有重要的应用价值。计算蛋白质设计可以根据所需的蛋白功能和结构设计氨基酸序列，生成自然界中不存在的蛋白质。传统计算蛋白质设计通常采用能量函数和特定的搜索优化算法获得设计的序列。近年来，随着先进算法的发展、大数据的积累和计算机硬件算力的增长，人工智能技术得到了蓬勃发展，并逐渐应用于蛋白质设计领域。本文综述了近年人工智能在蛋白质结构设计中的进展，侧重于各类算法的介绍，从固定骨架设计、可变骨架设计和序列结构生成三个方面回顾了最新的蛋白质结构设计算法，并阐明了其相对于传统计算方法的新颖性和创新性。在人工智能技术的赋能下，蛋白质设计的成功率和合理性获得大幅提高，按需功能蛋白设计的时代即将到来。

关键词: 蛋白质设计, 蛋白质工程, 人工智能, 深度学习, 蛋白质序列与结构

Abstract:

Proteins are essential to life as they carry out a great variety of biological functions. Protein sequences determine their three-dimensional structures, and therefore physiological functions. Proteins with specific functions have important applications in many fields such as biomedicine, where they are utilized in drug design and delivery. In the past, protein engineering and directed evolution are commonly used to improve the activity and stability of proteins. These methods, however, are both complex and expensive, as they require a large number of biological experiments for validation. Computational protein design (CPD) allows the design of amino acid sequences based on desired protein functions and structures, and more intriguingly, generation of proteins even not found in nature. Conventional CPD uses energy function and optimization algorithm to design protein sequences. In recent years, with the rapid development of artificial intelligence (AI) technique, the accumulation of big data and the development of high speed computing, AI has made great progresses in learning, and been successfully applied in CPD. In this review, based on the input constraints and sampling space size, we present a systematic overview of recent applications of AI in protein design from three aspects: fixed-backbone design, flexible-backbone design, and sequence structure generation. We focus on algorithms and protein feature encoding, present the effect of dataset size and architectural improvements on model performance in prediction, and showcase several enzymes, antibodies, and binding proteins that were successfully designed using these models. The advantages of AI compared with traditional CPD methods are also discussed. Finally, we highlight challenges in AI-aided protein design, and propose some strategies for solutions.

Key words: protein design, protein engineering, artificial intelligence, deep learning, protein sequence and structure

中图分类号:

Q816

陈志航, 季梦麟, 戚逸飞. 人工智能蛋白质结构设计算法研究进展[J]. 合成生物学, 2023, 4(3): 464-487.

Zhihang CHEN, Menglin JI, Yifei QI. Research progress of artificial intelligence in desiging protein structures[J]. Synthetic Biology Journal, 2023, 4(3): 464-487.

图/表 19

图1 SPROF中残基距离计算方法（a）dij 为残基i和j的Cα原子之间的距离，d0=0.4 nm；（b）蛋白质残基-残基距离矩阵

Fig. 1 Calculating the distance of residues in SPROF(a) dij is the distance between the Cα atoms of residues i and j, d0=0.4 nm, and (b) matrix for residue-residue distance of a protein structure.

图2 三维卷积神经网络提取网格中的蛋白质空间结构信息

Fig. 2 Extracting spatial information of a protein structure from 3D convolutional neural network

图3 trDesign模型架构图

Fig. 3 Architecture for the trDesign model

图 4 GraphTrans编码器与解码器示意图

Fig. 4 Architecture for the GraphTrans encoder and decoder

图5 GVP原理示意图

Fig. 5 Architecture for GVP

图 6 ABACUS-R模型架构示意图

Fig. 6 Architecture for the ABACUS-R model

图 7 ProteinMPNN模型的整体结构

Fig. 7 Architecture for the ProteinMPNN model

表1 固定骨架序列设计模型在CATH 4.2测试集上的序列恢复率和困惑度

Table 1 Sequence recovery rate and perplexity of the fixed-backbone sequence design model on CATH 4.2 test set

模型 Models	恢复率/%(↑) Recovery/% (↑)	困惑度(↓) Perplexity (↓)
GraphTrans	35.82	6.63
StructGNN^[76]	37.1	6.49
GVP-GNN-large	39.20	6.17
GVP-GNN-Transformer	38.30	6.44
GVP-GNN-Transformer+AF2	51.60	4.01
ProteinMPNN	45.96	4.61
ProDesign	50.22	4.69
PiFold^[77]	50.22	4.62
LM-DESIGN^[75]（PiFold）	55.65	4.52

表2 固定骨架序列设计模型在TS50 &TS500测试集上的序列恢复率和困惑度

Table 2 Sequence recovery rate and perplexity of the fixed-backbone sequence design model on TS50 &TS500 test sets

模型类别 Group	模型 Models	TS50		TS500
模型类别 Group	模型 Models	恢复率/%(↑) Recovery/%(↑)	困惑度(↓) Perplexity(↓)	恢复率/%(↑) Recovery/%(↑)	困惑度(↓) Perplexity (↓)
MLP	SPIN	30.00	—	—	—
	SPIN2	34.00	—	—	—
	Wang’s model	33.00	—	—	—
CNN	SPROF	39.80	—	—	—
	ProDCoNN	46.50	—	—	—
	DenseCPD	50.71	—	55.53	—
GNN	StructGNN	43.89	5.40	45.69	4.98
	GraphTrans	42.20	5.60	44.66	5.16
	GVP-GNN	44.14	4.71	49.14	4.20
	GCA^[78]	47.02	5.09	47.74	4.72
	ADesign^[79]	48.36	5.25	49.23	4.93
	ProteinMPNN	54.43	3.93	58.08	3.53
	PiFold	58.72	3.86	60.42	3.44
	LM-DESIGN（PiFold）	57.89	3.50	67.78	3.19

图8 hallucination模型原理示意图

Fig. 8 Architecture for the hallucination model

图9 Constrained hallucination模型原理示意图

Fig. 9 Architecture for the Constrained hallucination model

图10 生成对抗模型用于蛋白二维接触图和三维骨架的生成

Fig. 10 Generative adversarial network for generating contact map and 3D backbone structure.

图11 Famliy-wide幻想蛋白质结构生成模型架构图

Fig. 11 Architectuer for the famliy-wide hallucination protein structure generation model

图12 Ig-VAE模型架构

Fig. 12 Framwork for Ig-VAE

图 13 蛋白质结构生成扩散模型的原理示意图［100］

Fig. 13 Schematic diagram of the diffusion model for protein structure generation[100]

图14 FoldingDiff训练流程

Fig. 14 Training flow of the FoldingDiff model

图15 ProteinSGM蛋白编码和模型架构图

Fig. 15 Protein structure encoding and model architecture of ProteinSGM

图 16 RFdiffusion模型原理示意图

Fig. 16 Schematic diagram of the RFdiffusion model

图17 ProteinGAN基本架构

Fig. 17 Architecture for ProteinGAN

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