不精炼的配体占用率掩盖了蛋白质结合部位的异质性
Timothy R Stachowski1, Marcus Fischer1
1Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Structure (London, England : 1993)
|March 12, 2026
概括
许多蛋白质连接体结构错误地假定连接体占用完全. 重新精制10,000个结构显示35%的部分占用,揭示了隐藏的绑定站点灵活性和动态,这对于AI/ML应用至关重要.
科学领域:
- 结构生物学 结构生物学
- 计算化学的计算化学
- 药物发现 药物发现 药物发现
背景情况:
- 蛋白质-配体共晶结构通常假定完全的配体结合.
- 这种假设可以掩盖结合点的真实结构动态和结合/不结合状态的共存.
- 准确的对联体占用率建模对于理解蛋白质功能和下游应用,如AI/ML药物设计至关重要.
研究的目的:
- 为了研究在沉积的蛋白质-连接体结构中亚静态度连接体结合的流行情况.
- 突出不准确的占用率建模对理解绑定站点异质性的影响.
- 倡导改善结构生物学中的建模实践.
主要方法:
- 在大约1万个公开沉积的蛋白质-联结体共晶结构中重新精制联结体占用.
- 分析结构异质性,包括替代侧链形状,移动水网络和额外的连接体位置.
- 评估标准模型质量指标在检测占用不准确性的有效性.
主要成果:
- 35%的分析结构含有部分被占用的连接体,与原来的占用分配相比增加了3倍.
- 确定了被忽视的结构异质性,例如替代侧链构造和移动的水网.
- 精细的模型揭示了以前不被赞赏的结合事件,包括在全位.
- 标准质量指标往往无法标记这些占用模型的不准确性.
结论:
- 很大一部分蛋白质连接体结构是以不准确的连接体占用率建模的.
- 改进对联体占用量的建模对于全面了解蛋白质-联体相互作用和结合部位灵活性至关重要.
- 采用更严格的精细化实践将提高结构数据的可靠性,用于药物发现和AI/ML开发.
相关概念视频
02:40Ligand Binding Sites
15.6K
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...
15.6K
02:40Ligand Binding Sites
9.0K
9.0K
00:49Ligand Binding and Linkage
5.9K
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...
5.9K
00:49Ligand Binding and Linkage
4.2K
4.2K
01:49Conserved Binding Sites
5.3K
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...
5.3K
01:49Conserved Binding Sites
2.0K
2.0K