机器学习和计算机模拟解开了Hsp90的模糊抑制剂结合
Mohammad Sahil1, Jaya Krishna Koneru1, Jagannath Mondal1
1Tata Institute of Fundamental Research Hyderabad, 36/P Gopanapalli Village, Hyderabad TS-500046, India.
Journal of chemical theory and computation
|February 13, 2026
概括
我们使用先进的模拟和机器学习解决了凝丹胺素与热冲击蛋白90 (Hsp90) 的复杂结合机制,揭示了药物设计中关键的中间状态.
科学领域:
- 生物物理学的生物物理.
- 计算化学的计算化学
- 结构生物学 结构生物学
背景情况:
- 热冲击蛋白90 (Hsp90) 是一种重要的癌症点.
- 对Hsp90抑制剂的结晶学和NMR数据冲突使药物设计复杂化.
研究的目的:
- 为了阐明凝胺氨酸 (GDM) 与N-Hsp90.0.的结合机制.
- 为了调和Hsp90抑制剂结合模型中的结构差异.
主要方法:
- >100微秒的全原子分子动力学 (MD) 模拟.
- 混合适应模拟策略和 τ 随机加速 MD.
- 马尔科夫状态建模和漏斗元动力学模拟.
- 可解释的机器学习用于机械归因.
主要成果:
- 一种长寿命的中间状态主导着GDM结合通路到Hsp90.
- 该中间体在过渡到"循环出"束状态之前表现出"循环入"形态.
- 结合的自由能量与实验数据一致.
- 机器学习在残留物水平上确定了不同的形状选择和诱导适合机制.
结论:
- 这项研究解决了Hsp90抑制剂结合的长期结构差异.
- 建议采用一个以中间体为中心的结合机制.
- 这一框架为准像Hsp90.0这样的动态蛋白提供了一个蓝图.
相关概念视频
Eukaryotic Transcription Inhibitors
11.1K
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.1K
Machines
581
Machines are complex structures consisting of movable, pin-connected multi-force members that work together to transmit forces. One example of a machine is the cutting plier, which is used to cut wires by applying forces to its handles. When equal and opposite forces are exerted on the handles of the cutting plier, they cause the cutting edges to come together and apply equal and opposite reaction forces on the wire, which are greater than the applied forces.
A free-body diagram of the...
A free-body diagram of the...
581
The Equilibrium Binding Constant and Binding Strength
15.2K
The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
15.2K
Machines: Problem Solving II
678
Machines are complex structures consisting of movable, pin-connected multi-force members that work together to transmit forces. Consider a lifting tong carrying a 100 kg load. It comprises movable sections DAF and CBG linked together with member AB.
678
Machines: Problem Solving I
727
A toggle clamp is a mechanical device commonly used for holding and clamping objects in various applications, such as woodworking, metalworking, and assembly operations. Consider a toggle clamp subjected to a force of 200 N at the handle. The vertical clamping force can be calculated, provided the dimensions of the toggle clamp are known.
The toggle clamp system is a machine structure consisting of movable, pin-connected multi-force members that form a stabilized system to transmit forces. The...
The toggle clamp system is a machine structure consisting of movable, pin-connected multi-force members that form a stabilized system to transmit forces. The...
727
Ligand Binding Sites
15.2K
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...
15.2K


