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Electrostatics in the Stability and Misfolding of the Prion Protein: Salt Bridges, Self-Energy, and Solvation
Using a recently developed mesoscopic theory of protein dielectrics, we have
calculated the salt bridge energies, total residue electrostatic potential
energies, and transfer energies into a low dielectric amyloid-like phase for 12
species and mutants of the prion protein. Salt bridges and self energies play
key roles in stabilizing secondary and tertiary structural elements of the
prion protein. The total electrostatic potential energy of each residue was
found to be invariably stabilizing. Residues frequently found to be mutated in
familial prion disease were among those with the largest electrostatic
energies. The large barrier to charged group desolvation imposes regional
constraints on involvement of the prion protein in an amyloid aggregate,
resulting in an electrostatic amyloid recruitment profile that favours regions
of sequence between alpha helix 1 and beta strand 2, the middles of helices 2
and 3, and the region N-terminal to alpha helix 1. We found that the
stabilization due to salt bridges is minimal among the proteins studied for
disease-susceptible human mutants of prion protein
Workers’ Rights: A Winding Road in the Trucking Dispute Between the United States and Mexico
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