Electrostatics in the stability and misfolding of the prion protein: salt bridges, self energy, and solvation1
نویسندگان
چکیده
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 a helix 1 and b strand 2, the middles of helices 2 and 3, and the region N-terminal to a 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.
منابع مشابه
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 protei...
متن کاملIntroducing critical residues in the human prion protein and its Asp 178 Asn mutant by molecular dynamics simulation
The molecular dynamics (MD) simulation method is used to assess structural details for humanprion protein (hereafter PrPN) and its Asp178 Asn mutant (hereafter PrPm) which causes fatalfamilial insomnia disease. The results reveal that the flexibility and instability increase in PrPmcould be related to specific amino acids exposed to the solvent. Solvation free energy of PrPm is 20kjmot1nni2 mor...
متن کاملA Study on The Effect of Temperature on Human Prion Protein Structure through Molecular Dynamic Simulation
Background & Aims: The normal form of the prion protein is called PrPC and its infectious form is called PrPSc. This protein functions like a crystallized core for the transformation of PrPc into an abnormal PrPSc. The aim of the present study was to investigate the effect of temperature on human prion protein structure through molecular dynamic simulation. Methods: In this research, the GROMAC...
متن کاملThe structural stability of wild-type horse prion protein.
Prion diseases (e.g. Creutzfeldt-Jakob disease (CJD), variant CJD (vCJD), Gerstmann-Straussler-Scheinker syndrome (GSS), Fatal Familial Insomnia (FFI) and Kuru in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE or 'mad-cow' disease) and chronic wasting disease (CWD) in cattles) are invariably fatal and highly infectious neurodegenerative diseases affecting humans and animals. Ho...
متن کاملStability constraints and protein evolution: the role of chain length, composition and disulfide bonds.
Stability of the native state is an essential requirement in protein evolution and design. Here we investigated the interplay between chain length and stability constraints using a simple model of protein folding and a statistical study of the Protein Data Bank. We distinguish two types of stability of the native state: with respect to the unfolded state (unfolding stability) and with respect t...
متن کامل