Insufficient hydrogen-bond desolvation and prion-related disease.
A structuring and eventual exclusion of water surrounding backbone hydrogen bonds takes place during protein folding as hydrophobic residues cluster around such bonds. Taken as an average over all hydrogen bonds, the extent of desolvation is nearly a constant of motion, as revealed by re-examination of the longest all-atom trajectory with explicit solvent [Y. Duan & P. A. Kollman (1998) Science 282, 740]. Furthermore, this extent of desolvation is preserved across native soluble proteins, except for cellular prion proteins. Thus, a physico-chemical picture of prion-related disease emerges. The epitope for protein-X binding, the region undergoing vast conformational change and the trigger and locker for this change are inferred from the location of under-desolvated hydrogen bonds in the cellular prion protein.
Fernández
Ariel
A
Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. ariel@uchicago.edu
D000818:Animals; D006224:Cricetinae; D006801:Humans; D006860:Hydrogen Bonding; D008647:Mesocricetus; D018621:PrPC Proteins / Q000737:chemistry*; D018620:PrPSc Proteins / Q000737:chemistry*; D017096:Prion Diseases / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D012995:Solubility
D018621:PrPC Proteins; D018620:PrPSc Proteins