Thermodynamic and Kinetic Origins of Alzheimer's and Related Diseases: a Chemical Engineer's Perspective Carol K. Hall Department of Chemical & Biomolecular Engineering North Carolina State University http://turbo.che.ncsu.edu. Protein Folding: The ABCs.
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Thermodynamic and Kinetic Origins of Alzheimer's and Related Diseases: a Chemical Engineer's PerspectiveCarol K. HallDepartment of Chemical & Biomolecular Engineering North Carolina State University http://turbo.che.ncsu.edu
A. A protein is a chain of amino acid residues arranged in a unique sequence.
Villin headpiece protein
(moderate T or low denaturant)
D. Proteins unfold into a “random coil” if temperature raised or denaturant (urea, GuHCl) added.
E. Of all the forces thought to govern protein folding, hydrophobicity and hydrogen bonding are considered most important.
(high T or high denaturant)
Prion disease (e.g. Mad Cow)
Amyloid Lateral Sclerosis
( Lou Gehrig’s)
HuntingtinAmyloidoses:Diseases characterized by the abnormal aggregation of proteins into ordered structures, called “fibrils” or “amyloid.”
50% of 85+ year olds
To develop a computational tool that :
allows investigation (particularly visualization) of spontaneous fibril formation.
reveals the basic physical principles underlying fibril formation
Six Blind Men and Elephant
Speculation - fibril formation is natural consequence of peptide geometry, hydrogen-bonding capability and hydrophobic interactions under slightly-denatured, concentrated conditions.
Polyalanine peptides form fibrils in vitro at high concentrations (C > 1.5 mM) and high temperature (T > 40oC) (Blondelle et al., Biochem. 1997).
Peptide Sequence: KA14K
beta-sheets in a fibril
Packages: Amber, CHARMm, ENCAD, ECEPP, Discover, UNRES, etc.
Force fields: describe interactions between all atoms on protein and in solvent at atomic resolution
Desired Output: “folding” trajectory of a protein
Limitation: very difficult to simulate folding of a single protein even with the fastest computers
Implications : sacrifice details to study protein aggregation
Forces based on Lennard Jones (LJ) potential.
Follow particle trajectories by numerically integrating Newton’s 2nd law every picosecond.
Forces field based on square-well potential.
Follow particle trajectories by analytically integrating Newton’s 2nd law
Particles move linearly between collisons, capture or bounce
NHPRIME (Protein Intermediate Resolution Model):
R= CH3 for alanine
hard spheres with realistic diameters
ideal backbone bond angles
Smith and Hall. PROTEINS (2001) 44 344
Nguyen et al. Protein Sci (2004) 13 2909-2924
Hydrogen bonds between backbone amine and carbonyl groups are modeled with a directional square-well attraction of strength eH-bonding.
Define reduced temperature as: T*=kBT/εH-bonding
Nguyen,Marchut & Hall Biophys. J (2004)
Nguyen & Hall, PNAS (2005)
Use the replica-exchange method to simulate 96-peptide systems at different temperatures and peptide concentrations.
These trends qualitatively agree with experimental data (Blondelle 1997)
Nguyen & Hall Biophys. J. (2004)
Intra-sheet distance: 4.92 ± 0.01A, comparable to experimental values of 4.76A (Shinchuk et al., Proteins, 2005)
Inter-sheet distance: 7.52 ± 0.23A, comparable to experimental values of 5.4A (Shinchuck et al., Proteins, 2005)
Most peptides are in-register, same as experimental results for the A-ß(10-35) peptide (Benzinger et al., PNAS 1998)
Nguyen & Hall, J. Biol. Chem (2005)
Adding a seed eliminates the fibril formation lag time, as found experimentally.