相关实验视频

Updated: Jun 15, 2025

Microfluidic Mixers for Studying Protein Folding

Microfluidic Mixers for Studying Protein Folding

Published on: April 10, 2012

折叠交换形状的AlphaFold预测是由结构记忆驱动的

Devlina Chakravarty¹, Joseph W Schafer¹, Ethan A Chen¹

¹National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, 20894, USA.

Nature communications

|August 24, 2024

概括

像AlphaFold这样的深度学习模型难以预测蛋白质折叠切换,经常记住训练数据,而不是学习蛋白质能量. 需要基于物理的方法来准确预测多种蛋白质构造.

科学领域:

蛋白质结构预测蛋白质结构预测
计算生物学是一种计算生物学.
生物物理学的生物物理.

背景情况:

深度学习模型,如AlphaFold (AF),已经显示出从序列预测蛋白质结构的前景.
蛋白质能量格局,以形状多样性为特征,对于理解蛋白质功能至关重要.
折叠切换蛋白质具有挑战性,因为它们能够采用多个不同的结构.

研究的目的:

为了评估AlphaFold对折叠切换蛋白的预测能力.
为了确定AlphaFold是否可以准确地模拟蛋白质能量景观和结构动态.
确定深度学习模型在预测复杂蛋白质行为方面的局限性.

主要方法:

在已知的折叠切换蛋白质上测试AlphaFold (AF2和AF3).
从多个AlphaFold实现中分析了超过56万个预测模型.
将预测与实验确定结构进行比较,并评估AlphaFold的信心指标.
调查潜在的训练数据记忆和共同进化约束的错误分配.

主要成果:

阿尔法折叠表明蛋白质折叠切换的预测能力较弱.
对于AlphaFold在折叠切换蛋白的成功,很大一部分来自于对训练数据的记忆.
对于识别正确的折叠交换形状,AlphaFold的信心指标是不可靠的.
对于训练组中的蛋白质,性能仅为35%的成功,而对于训练组之外的蛋白质,仅为7分之一的成功.

结论:

目前的深度学习模型,如AlphaFold在预测蛋白质折叠切换方面存在重大局限性.
这些模型似乎记住结构信息,而不是学习潜在的生物物理原理.
需要基于物理的计算方法来准确预测多种蛋白质构造和能量景观.

更多相关视频

A Protocol for Computer-Based Protein Structure and Function Prediction

A Protocol for Computer-Based Protein Structure and Function Prediction

Published on: November 3, 2011

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules

Published on: July 25, 2013

相关概念视频

Protein Folding

Protein Folding

Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...

Molecular Chaperones and Protein Folding

Molecular Chaperones and Protein Folding

The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...

Amyloid Fibrils

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...

Conservation of Protein Domains Over Different Proteins

Conservation of Protein Domains Over Different Proteins

Protein domains are small structurally independent units that are part of a single amino acid chain. Although these domains are often structurally independent, they may rely on synergistic effects to perform their functions as part of a larger protein. Protein domains may be conserved within the same organism, as well as across different organisms.
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to...

Cooperative Allosteric Transitions

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...

Conserved Binding Sites

Conserved Binding Sites

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...