Proline isomerization effects in the amyloidogenic protein ß2-microglobulin.
Phys Chem Chem Phys
; 23(1): 356-367, 2021 Jan 06.
Article
in En
| MEDLINE
| ID: mdl-33346272
ABSTRACT
The protein ß2-microglobulin (ß2-m) can aggregate in insoluble amyloid fibrils, which deposit in the skeletal muscle system of patients undergoing long-term haemodialysis. The molecular mechanisms of such amyloidogenesis are still not fully understood. A potential, although debated, triggering factor is the cis to trans isomerization of a specific proline (Pro32) in ß2-m. Here we investigate this process in the native protein and in the aggregation-prone mutant D76N by means of molecular dynamics and the enhanced sampling method metadynamics. Our simulations, including the estimation of the free energy difference between the cis and trans isomers, are in good agreement with in vitro experiments and highlight the importance of the hydrogen bond and hydrophobic interaction network around the critical Pro32 in stabilizing and de-stabilizing the two isomers.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proline
/
Beta 2-Microglobulin
/
Amyloidogenic Proteins
Limits:
Humans
Language:
En
Journal:
Phys Chem Chem Phys
Journal subject:
BIOFISICA
/
QUIMICA
Year:
2021
Document type:
Article
Affiliation country: