Theoretical analysis on thermodynamic stability of chignolin

Research output: Contribution to journalArticle

Abstract

Understanding the dominant factor in thermodynamic stability of proteins remains an open challenge. Kauzmann’s hydrophobic interaction hypothesis, which considers hydrophobic interactions between nonpolar groups as the dominant factor, has been widely accepted for about sixty years and attracted many scientists. The hypothesis, however, has not been verified or disproved because it is difficult, both theoretically and experimentally, to quantify the solvent effects on the free energy change in protein folding. Here, we developed a computational method for extracting the dominant factor behind thermodynamic stability of proteins and applied it to a small, designed protein, chignolin. The resulting free energy profile quantitatively agreed with the molecular dynamics simulations. Decomposition of the free energy profile indicated that intramolecular interactions predominantly stabilized collapsed conformations, whereas solvent-induced interactions, including hydrophobic ones, destabilized them. These results obtained for chignolin were consistent with the site-directed mutagenesis and calorimetry experiments for globular proteins with hydrophobic interior cores.

Original languageEnglish
Article number5186
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

Fingerprint

Thermodynamic stability
Free energy
Proteins
Protein folding
Mutagenesis
Calorimetry
Computational methods
Conformations
Molecular dynamics
Decomposition
chignolin
Computer simulation
Experiments

ASJC Scopus subject areas

  • General

Cite this

Theoretical analysis on thermodynamic stability of chignolin. / Sumi, Tomonari; Koga, Kenichiro.

In: Scientific reports, Vol. 9, No. 1, 5186, 01.12.2019.

Research output: Contribution to journalArticle

@article{939739305a8248cb854c7a8ced513d9e,
title = "Theoretical analysis on thermodynamic stability of chignolin",
abstract = "Understanding the dominant factor in thermodynamic stability of proteins remains an open challenge. Kauzmann’s hydrophobic interaction hypothesis, which considers hydrophobic interactions between nonpolar groups as the dominant factor, has been widely accepted for about sixty years and attracted many scientists. The hypothesis, however, has not been verified or disproved because it is difficult, both theoretically and experimentally, to quantify the solvent effects on the free energy change in protein folding. Here, we developed a computational method for extracting the dominant factor behind thermodynamic stability of proteins and applied it to a small, designed protein, chignolin. The resulting free energy profile quantitatively agreed with the molecular dynamics simulations. Decomposition of the free energy profile indicated that intramolecular interactions predominantly stabilized collapsed conformations, whereas solvent-induced interactions, including hydrophobic ones, destabilized them. These results obtained for chignolin were consistent with the site-directed mutagenesis and calorimetry experiments for globular proteins with hydrophobic interior cores.",
author = "Tomonari Sumi and Kenichiro Koga",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-019-41518-1",
language = "English",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Theoretical analysis on thermodynamic stability of chignolin

AU - Sumi, Tomonari

AU - Koga, Kenichiro

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Understanding the dominant factor in thermodynamic stability of proteins remains an open challenge. Kauzmann’s hydrophobic interaction hypothesis, which considers hydrophobic interactions between nonpolar groups as the dominant factor, has been widely accepted for about sixty years and attracted many scientists. The hypothesis, however, has not been verified or disproved because it is difficult, both theoretically and experimentally, to quantify the solvent effects on the free energy change in protein folding. Here, we developed a computational method for extracting the dominant factor behind thermodynamic stability of proteins and applied it to a small, designed protein, chignolin. The resulting free energy profile quantitatively agreed with the molecular dynamics simulations. Decomposition of the free energy profile indicated that intramolecular interactions predominantly stabilized collapsed conformations, whereas solvent-induced interactions, including hydrophobic ones, destabilized them. These results obtained for chignolin were consistent with the site-directed mutagenesis and calorimetry experiments for globular proteins with hydrophobic interior cores.

AB - Understanding the dominant factor in thermodynamic stability of proteins remains an open challenge. Kauzmann’s hydrophobic interaction hypothesis, which considers hydrophobic interactions between nonpolar groups as the dominant factor, has been widely accepted for about sixty years and attracted many scientists. The hypothesis, however, has not been verified or disproved because it is difficult, both theoretically and experimentally, to quantify the solvent effects on the free energy change in protein folding. Here, we developed a computational method for extracting the dominant factor behind thermodynamic stability of proteins and applied it to a small, designed protein, chignolin. The resulting free energy profile quantitatively agreed with the molecular dynamics simulations. Decomposition of the free energy profile indicated that intramolecular interactions predominantly stabilized collapsed conformations, whereas solvent-induced interactions, including hydrophobic ones, destabilized them. These results obtained for chignolin were consistent with the site-directed mutagenesis and calorimetry experiments for globular proteins with hydrophobic interior cores.

UR - http://www.scopus.com/inward/record.url?scp=85063505518&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063505518&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-41518-1

DO - 10.1038/s41598-019-41518-1

M3 - Article

C2 - 30914684

AN - SCOPUS:85063505518

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 5186

ER -