Towards a "Golden Standard" for computing globin stability: Stability and structure sensitivity of myoglobin mutants

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Fast and accurate computation of protein stability is increasingly important for e.g. protein engineering and protein misfolding diseases, but no consensus methods exist for important proteins such as globins, and performance may depend on the type of structural input given. This paper reports benchmarking of six protein stability calculators (POPMUSIC 2.1, I-Mutant 2.0, I-Mutant 3.0, CUPSAT, SDM, and mCSM) against 134 experimental stability changes for mutations of sperm-whale myoglobin. Six different high-resolution structures were used to test structure sensitivity that may impair protein calculations. The trend accuracy of the methods decreased as I-Mutant 2.0 (R=0.64-0.65), SDM (R=0.57-0.60), POPMUSIC2.1 (R=0.54-0.57), I-Mutant 3.0 (R=0.53-0.55), mCSM (R=0.35-0.47), and CUPSAT (R=0.25-0.48). The mean signed errors increased as SDM<CUPSAT<I-Mutant 2.0<I-Mutant 3.0<POPMUSIC 2.1<mCSM. Mean absolute errors increased as I-Mutant 2.0<I-Mutant 3.0<POPMUSIC 2.1<CUPSAT<SDM<mCSM. Structural sensitivity increased as I-Mutant 3.0 (0.05)<I-Mutant 2.0 (0.09)<POPMUSIC 2.1 (0.12)<SDM (0.18)<mCSM (0.27)<CUPSAT (0.58). Leaving out heterogeneous experimental data did not change conclusions. The distinct performances reveal room for improvement, but I-Mutant 2.0 is proficient for this purpose, as further validated against a data set of related cytochrome c like proteins. The results also emphasize the importance of high-quality crystal structures and reveal structure-dependent effects even in the near-atomic resolution limit.
Original languageEnglish
JournalBBA Proteins and Proteomics
Volume1854
Issue number10, Part A
Pages (from-to)1239-1248
Number of pages10
ISSN1570-9639
DOIs
Publication statusPublished - 2015

Keywords

  • Myoglobin
  • Mutant stability
  • Protein calculation
  • High-resolution crystal structure
  • Structure sensitivity

Cite this

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title = "Towards a {"}Golden Standard{"} for computing globin stability: Stability and structure sensitivity of myoglobin mutants",
abstract = "Fast and accurate computation of protein stability is increasingly important for e.g. protein engineering and protein misfolding diseases, but no consensus methods exist for important proteins such as globins, and performance may depend on the type of structural input given. This paper reports benchmarking of six protein stability calculators (POPMUSIC 2.1, I-Mutant 2.0, I-Mutant 3.0, CUPSAT, SDM, and mCSM) against 134 experimental stability changes for mutations of sperm-whale myoglobin. Six different high-resolution structures were used to test structure sensitivity that may impair protein calculations. The trend accuracy of the methods decreased as I-Mutant 2.0 (R=0.64-0.65), SDM (R=0.57-0.60), POPMUSIC2.1 (R=0.54-0.57), I-Mutant 3.0 (R=0.53-0.55), mCSM (R=0.35-0.47), and CUPSAT (R=0.25-0.48). The mean signed errors increased as SDM<CUPSAT<I-Mutant 2.0<I-Mutant 3.0<POPMUSIC 2.1<mCSM. Mean absolute errors increased as I-Mutant 2.0<I-Mutant 3.0<POPMUSIC 2.1<CUPSAT<SDM<mCSM. Structural sensitivity increased as I-Mutant 3.0 (0.05)<I-Mutant 2.0 (0.09)<POPMUSIC 2.1 (0.12)<SDM (0.18)<mCSM (0.27)<CUPSAT (0.58). Leaving out heterogeneous experimental data did not change conclusions. The distinct performances reveal room for improvement, but I-Mutant 2.0 is proficient for this purpose, as further validated against a data set of related cytochrome c like proteins. The results also emphasize the importance of high-quality crystal structures and reveal structure-dependent effects even in the near-atomic resolution limit.",
keywords = "Myoglobin, Mutant stability, Protein calculation, High-resolution crystal structure, Structure sensitivity",
author = "Kepp, {Kasper Planeta}",
year = "2015",
doi = "10.1016/j.bbapap.2015.06.002",
language = "English",
volume = "1854",
pages = "1239--1248",
journal = "B B A - Proteins and Proteomics",
issn = "1570-9639",
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number = "10, Part A",

}

Towards a "Golden Standard" for computing globin stability: Stability and structure sensitivity of myoglobin mutants. / Kepp, Kasper Planeta.

In: BBA Proteins and Proteomics, Vol. 1854, No. 10, Part A, 2015, p. 1239-1248.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Towards a "Golden Standard" for computing globin stability: Stability and structure sensitivity of myoglobin mutants

AU - Kepp, Kasper Planeta

PY - 2015

Y1 - 2015

N2 - Fast and accurate computation of protein stability is increasingly important for e.g. protein engineering and protein misfolding diseases, but no consensus methods exist for important proteins such as globins, and performance may depend on the type of structural input given. This paper reports benchmarking of six protein stability calculators (POPMUSIC 2.1, I-Mutant 2.0, I-Mutant 3.0, CUPSAT, SDM, and mCSM) against 134 experimental stability changes for mutations of sperm-whale myoglobin. Six different high-resolution structures were used to test structure sensitivity that may impair protein calculations. The trend accuracy of the methods decreased as I-Mutant 2.0 (R=0.64-0.65), SDM (R=0.57-0.60), POPMUSIC2.1 (R=0.54-0.57), I-Mutant 3.0 (R=0.53-0.55), mCSM (R=0.35-0.47), and CUPSAT (R=0.25-0.48). The mean signed errors increased as SDM<CUPSAT<I-Mutant 2.0<I-Mutant 3.0<POPMUSIC 2.1<mCSM. Mean absolute errors increased as I-Mutant 2.0<I-Mutant 3.0<POPMUSIC 2.1<CUPSAT<SDM<mCSM. Structural sensitivity increased as I-Mutant 3.0 (0.05)<I-Mutant 2.0 (0.09)<POPMUSIC 2.1 (0.12)<SDM (0.18)<mCSM (0.27)<CUPSAT (0.58). Leaving out heterogeneous experimental data did not change conclusions. The distinct performances reveal room for improvement, but I-Mutant 2.0 is proficient for this purpose, as further validated against a data set of related cytochrome c like proteins. The results also emphasize the importance of high-quality crystal structures and reveal structure-dependent effects even in the near-atomic resolution limit.

AB - Fast and accurate computation of protein stability is increasingly important for e.g. protein engineering and protein misfolding diseases, but no consensus methods exist for important proteins such as globins, and performance may depend on the type of structural input given. This paper reports benchmarking of six protein stability calculators (POPMUSIC 2.1, I-Mutant 2.0, I-Mutant 3.0, CUPSAT, SDM, and mCSM) against 134 experimental stability changes for mutations of sperm-whale myoglobin. Six different high-resolution structures were used to test structure sensitivity that may impair protein calculations. The trend accuracy of the methods decreased as I-Mutant 2.0 (R=0.64-0.65), SDM (R=0.57-0.60), POPMUSIC2.1 (R=0.54-0.57), I-Mutant 3.0 (R=0.53-0.55), mCSM (R=0.35-0.47), and CUPSAT (R=0.25-0.48). The mean signed errors increased as SDM<CUPSAT<I-Mutant 2.0<I-Mutant 3.0<POPMUSIC 2.1<mCSM. Mean absolute errors increased as I-Mutant 2.0<I-Mutant 3.0<POPMUSIC 2.1<CUPSAT<SDM<mCSM. Structural sensitivity increased as I-Mutant 3.0 (0.05)<I-Mutant 2.0 (0.09)<POPMUSIC 2.1 (0.12)<SDM (0.18)<mCSM (0.27)<CUPSAT (0.58). Leaving out heterogeneous experimental data did not change conclusions. The distinct performances reveal room for improvement, but I-Mutant 2.0 is proficient for this purpose, as further validated against a data set of related cytochrome c like proteins. The results also emphasize the importance of high-quality crystal structures and reveal structure-dependent effects even in the near-atomic resolution limit.

KW - Myoglobin

KW - Mutant stability

KW - Protein calculation

KW - High-resolution crystal structure

KW - Structure sensitivity

U2 - 10.1016/j.bbapap.2015.06.002

DO - 10.1016/j.bbapap.2015.06.002

M3 - Journal article

VL - 1854

SP - 1239

EP - 1248

JO - B B A - Proteins and Proteomics

JF - B B A - Proteins and Proteomics

SN - 1570-9639

IS - 10, Part A

ER -