机器学习模型用于询问针对囊蛋白的全蛋白体共价结合性
Ruibin Liu1, Joseph Clayton1,2, Mingzhe Shen1
1Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
bioRxiv : the preprint server for biology
|September 4, 2023
概括
机器学习模型准确地识别了可共聚结合的部位,加速了针对性的共聚抑制剂设计. 这项工作通过预测新药发现的囊蛋白反应性来扩大可药性蛋白质组.
科学领域:
- 计算化学和结构生物学
- 药物发现和药物化学
- 生物信息学和机器学习
背景情况:
- 向的共价抑制剂为药物开发提供了一个有希望的途径,但确定合适的可结合部位仍然是一个挑战.
- 扩大可用药的蛋白质组需要新的方法来识别潜在的药物标.
- 机器学习 (ML) 方法有可能加速这些网站的识别.
研究的目的:
- 开发和验证可靠的机器学习模型,用于识别蛋白质中可共结合的位点.
- 为培训和测试ML模型创建一个有关联的半氨酸综合数据库.
- 为共价药物发现社区提供工具和资源.
主要方法:
- 策划了一种新型数据库 (LigCys3D),包含使用PDB结构的近800种蛋白质的1000多种联结型半氨酸.
- 在LigCys3D数据库上开发和训练基于树的模型和卷积神经网络 (CNN).
- 使用未见的测试数据和AlphaFold2预测结构的验证模型.
主要成果:
- 在未见数据上,树模型的AUC为94%,CNN的AUC为93%,实现了高性能.
- 在使用ML模型对预测结构进行回顾时,已证明超过90%的回忆率.
- 在包括PH和SH2域在内的392个人体激酶中确定并报告了可结合的预测性囊蛋白.
结论:
- 在精选数据上训练的ML模型可以可靠地识别共可结合的氨酸.
- 开发的工具 (LigCys3D数据库和DeepCys网络服务器) 将帮助研究人员发现共价药物.
- 这项工作代表了向下一代药物发现人类蛋白质组的ML驱动注释迈出的重要一步.
相关概念视频
02:40Ligand Binding Sites
12.9K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
12.9K
00:49Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K
01:49Conserved Binding Sites
4.2K
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
4.2K
02:04Protein-protein Interfaces
12.5K
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
12.5K
02:26Protein Networks
4.0K
An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
4.0K
02:04Covalently Linked Protein Regulators
6.8K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
6.8K