How significant is a protein structure similarity with TM-score = 0.5?
Open accessAbstract
Motivation: Protein structure similarity is often measured by root mean squared deviation, global distance test score and template modeling score (TM-score). However, the scores themselves cannot provide information on how significant the structural similarity is. Also, it lacks a quantitative relation between the scores and conventional fold classifications. This article aims to answer two questions: (i) what is the statistical significance of TM-score? (ii) What is the probability of two proteins having the same fold given a specific TM-score? Results: We first made an all-to-all gapless structural match on 6684 non-homologous single-domain proteins in the PDB and found that the TM-scores follow an extreme value distribution. The data allow us to assign each TM-score a P-value that measures the chance of two randomly selected proteins obtaining an equal or higher TM-score. With a TM-score at 0.5, for instance, its P-value is 5.5 × 10−7, which means we need to consider at least 1.8 million random protein pairs to acquire a TM-score of no less than 0.5. Second, we examine the posterior probability of the same fold proteins from three datasets SCOP, CATH and the consensus of SCOP and CATH. It is found that the posterior probability from different datasets has a similar rapid phase transition around TM-score=0.5. This finding indicates that TM-score can be used as an approximate but quantitative criterion for protein topology classification, i.e. protein pairs with a TM-score >0.5 are mostly in the same fold while those with a TM-score <0.5 are mainly not in the same fold. Contact: zhng@umich.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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The CoFeS structures share a common fold, confirming their homology.
“These scores indicate that the structures share a common fold, confirming their homology [115].”
From Evidence for corrin biosynthesis in the last universal common ancestor (2025) · cites this paper as [115]
Section 3.2.5 says TM-scores can indicate whether protein structures share a fold, but describes this as a probabilistic inference whose reliability depends on the score. The paper does not assess the CoFeS structures or say that sharing a fold confirms homology; the Discussion treats fold and homologous-family classifications as distinct levels. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTM-score >0.5 indicates correct global topology for structure models.
“TM-score ranges between 0 and 1, with TM-score > 0.5 meaning structure models of correct global topology.39”
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- Authors
- Xu, J., & Zhang, Y.
- Affiliations
- University of Kansas (US)
- Corresponding author
- Zhang, Yang
- Venue
- Bioinformatics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-02-17
- Volume
- 26
- Issue
- 7
- Pages
- 889-895
- ISSN
- 1367-4803 (ISSN-L)
- 1367-4811
- PMC
- PMC2913670
- OpenAlex
- W2115540209
- Cited by
- 1,142
- References
- 36
- Citations by year
- 2026: 170 · 2025: 184 · 2024: 142 · 2023: 82 · 2022: 71 · 2021: 84 · 2020: 48 · 2019: 73 · 2018: 40 · 2017: 39 · 2016: 38 · 2015: 47 · 2014: 31 · 2013: 40 · 2012: 29
- FWCI
- 11.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Bioinformatics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (0746198)
- Alfred P. Sloan Foundation
- National Institute of General Medical Sciences (GM-083107, R01GM084222, GM083107, GM084222, GM-084222, R01GM083107)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- TM-score, protein structural similarity, statistical significance, extreme value distribution, p-values, protein fold classification, protein topology, non-homologous proteins, single-domain proteins, SCOP, CATH, posterior probability
- MeSH terms
- Protein Conformation, Proteins, Protein Folding, Computational Biology, Databases, Protein
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