PABMB Lecture. Protein dynamics, folding and misfolding: from basic physical chemistry to human conformational diseases.
Proteins exhibit a variety of motions ranging from amino acid side-chain rotations to the motions of large domains. Recognition of their conformational flexibility has led to the view that protein molecules undergo fast dynamic interconversion between different conformational substates. This proposal has received support from a wide variety of experimental techniques and from computer simulations of protein dynamics. More recently, studies of the subunit dissociation of oligomeric proteins induced by hydrostatic pressure have shown that the characteristic times for subunit exchange between oligomers and for interconversion between different conformations may be rather slow (hours or days). In such cases, proteins cannot be treated as an ensemble of rapidly interconverting conformational substates, but rather as a persistently heterogeneous population of different long-lived conformers. This is reminiscent of the deterministic behavior exhibited by macroscopic bodies, and may have important implications for our understanding of protein folding and biological functions. Here, we propose that the deterministic behavior of proteins may be closely related to the genesis of conformational diseases, a class of pathological conditions that includes transmissible spongiform encephalopathies, Alzheimer's disease and other amyloidosis.
Ferreira
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ST
Departamento de Bioquímica Médica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21944-590, Rio de Janeiro, Brazil. ferreira@bioqmed.ufrj.br
De Felice
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FG
D000686:Amyloidosis / Q000503:physiopathology; D000818:Animals; D002493:Central Nervous System Diseases / Q000503:physiopathology*; D006801:Humans; D008954:Models, Biological; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D014305:Triose-Phosphate Isomerase / Q000737:chemistry
D011506:Proteins; D014305:Triose-Phosphate Isomerase