Dataset Information

Unfolding Pathways of Hen Egg-White Lysozyme in Ethanol.

ABSTRACT: The aggregation of amyloid fibrils can lead to various diseases including Alzheimer's, Parkinson's disease, and transmissible spongiform encephalopathy. Amyloid fibrils can develop from a variety of proteins in the body as they misfold into a primarily β-sheet structure and aggregate. Human lysozyme has been shown to have far reaching effects in the human health-a homologous enzyme, hen egg-white lysozyme, has been shown to denature to a primarily β-sheet structure at low pH and high alcohol content solution. We have studied these systems in atomic-level detail with a combination of constant pH and microsecond long molecular dynamics simulation in explicit solvent, which cumulatively total over 10 μs of simulation time. These studies have allowed us to determine two potential unfolding pathways depending on the protonation state of a key glutamic acid residue as well as the effect of solution dynamics and pH on the unfolding process.

SUBMITTER: Walker AR

PROVIDER: S-EPMC10405640 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Unfolding Pathways of Hen Egg-White Lysozyme in Ethanol.

Walker Alice R AR Baddam Nikhil N Cisneros G Andrés GA

The journal of physical chemistry. B 20190404 15

The aggregation of amyloid fibrils can lead to various diseases including Alzheimer's, Parkinson's disease, and transmissible spongiform encephalopathy. Amyloid fibrils can develop from a variety of proteins in the body as they misfold into a primarily β-sheet structure and aggregate. Human lysozyme has been shown to have far reaching effects in the human health-a homologous enzyme, hen egg-white lysozyme, has been shown to denature to a primarily β-sheet structure at low pH and high alcohol con ...[more]

PMID: 30912946

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Project description:Chemical bonding at the active site of hen egg-white lysozyme (HEWL) is analyzed on the basis of Bader's quantum theory of atoms in molecules [QTAIM; Bader (1994), Atoms in Molecules: A Quantum Theory. Oxford University Press] applied to electron-density maps derived from a multipole model. The observation is made that the atomic displacement parameters (ADPs) of HEWL at a temperature of 100 K are larger than ADPs in crystals of small biological molecules at 298 K. This feature shows that the ADPs in the cold crystals of HEWL reflect frozen-in disorder rather than thermal vibrations of the atoms. Directly generalizing the results of multipole studies on small-molecule crystals, the important consequence for electron-density analysis of protein crystals is that multipole parameters cannot be independently varied in a meaningful way in structure refinements. Instead, a multipole model for HEWL has been developed by refinement of atomic coordinates and ADPs against the X-ray diffraction data of Wang and coworkers [Wang et al. (2007), Acta Cryst. D63, 1254-1268], while multipole parameters were fixed to the values for transferable multipole parameters from the ELMAM2 database [Domagala et al. (2012), Acta Cryst. A68, 337-351] . Static and dynamic electron densities based on this multipole model are presented. Analysis of their topological properties according to the QTAIM shows that the covalent bonds possess similar properties to the covalent bonds of small molecules. Hydrogen bonds of intermediate strength are identified for the Glu35 and Asp52 residues, which are considered to be essential parts of the active site of HEWL. Furthermore, a series of weak C-H...O hydrogen bonds are identified by means of the existence of bond critical points (BCPs) in the multipole electron density. It is proposed that these weak interactions might be important for defining the tertiary structure and activity of HEWL. The deprotonated state of Glu35 prevents a distinction between the Phillips and Koshland mechanisms.

Dataset Information

Unfolding Pathways of Hen Egg-White Lysozyme in Ethanol.

Publications

Unfolding Pathways of Hen Egg-White Lysozyme in Ethanol.

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