Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 52, Pages 21057-21062Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1112197108
Keywords
protein misfolding; free energy barriers; avoidance of protein aggregation; molecular simulations
Categories
Funding
- Medical Research Council
- Engineering and Physical Sciences Research Council
- European Molecular Biology Organization
- Marie Curie
- Human Science Frontier Program
- Italian Ministero dell'Istruzione dell'Universita e della Ricerca
- Boehringer Ingelheim Foundation
- Murray Edwards College, Cambridge
- National Science Council of the Republic of China-Taiwan
- Biotechnology and Biological Sciences Research Council
- Royal Society
- BBSRC [BB/H003843/1] Funding Source: UKRI
- EPSRC [EP/G049998/2] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H003843/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/G049998/2] Funding Source: researchfish
Ask authors/readers for more resources
The identification of the factors that enable normally folded proteins to remain in their soluble and functional states is crucial for a comprehensive understanding of any biological system. We have determined a series of energy landscapes of the acylphosphatase from Drosophila melanogaster under a variety of conditions by combining NMR measurements with restrained molecular dynamics simulations. We thus analyzed the differences in the structures, dynamics, and energy surfaces of the protein in its soluble state or in situations where it aggregates through conformational states that have native-like structure, folding stability, and enzymatic activity. The study identifies the nature of the energy barriers that under normal physiological conditions prevent the protein ensemble from populating dangerous aggregation-prone states. We found that such states, although similar to the native conformation, have altered surface charge distribution, alternative topologies of the beta-sheet region, and modified solvent exposure of hydrophobic surfaces and aggregation-prone regions of the sequence. The identified barriers allow the protein to undergo functional dynamics while remaining soluble and without a significant risk of misfolding and aggregation into nonfunctional and potentially toxic species.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available