Structural and Thermodynamic Characteristics of Amyloidogenic Intermediates of β-2-Microglobulin

Scientific Reports
Song-Ho ChongSihyun Ham

Abstract

β-2-microglobulin (β2m) self-aggregates to form amyloid fibril in renal patients taking long-term dialysis treatment. Despite the extensive structural and mutation studies carried out so far, the molecular details on the factors that dictate amyloidogenic potential of β2m remain elusive. Here we report molecular dynamics simulations followed by the solvation thermodynamic analyses on the wild-type β2m and D76N, D59P, and W60C mutants at the native (N) and so-called aggregation-prone intermediate (IT) states, which are distinguished by the native cis- and non-native trans-Pro32 backbone conformations. Three major structural and thermodynamic characteristics of the IT-state relative to the N-state in β2m protein are detected that contribute to the increased amyloidogenic potential: (i) the disruption of the edge D-strand, (ii) the increased solvent-exposed hydrophobic interface, and (iii) the increased solvation free energy (less affinity toward solvent water). Mutation effects on these three factors are shown to exhibit a good correlation with the experimentally observed distinct amyloidogenic propensity of the D76N (+), D59P (+), and W60C (-) mutants (+/- for enhanced/decreased). Our analyses thus identify the structural and th...Continue Reading

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Citations

Oct 21, 2017·Molecular BioSystems·Cedrix J Dongmo FoumthuimFederico Fogolari
Jul 15, 2020·The Journal of Biological Chemistry·Hugh I SmithSheena E Radford
Feb 16, 2021·Journal of the American Society for Mass Spectrometry·Owen CornwellAlison E Ashcroft
Nov 3, 2020·Frontiers in Molecular Biosciences·Rui J S Loureiro, Patrícia F N Faísca
Mar 13, 2018·The Journal of Physical Chemistry. B·Yutaka Maruyama, Ayori Mitsutake

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Methods Mentioned

BETA
X-ray

Software Mentioned

Swiss PDB Viewer
AMBER12

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