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

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 thermodynamic characteristics of the amyloidogenic intermediates, which will serve to uncover molecular mechanisms and driving forces in β2m amyloid fibril formation.

The Early Phase of β2-Microglobulin Aggregation: Perspectives From Molecular Simulations

“…Furthermore, since the number of replicas increases markedly with system’s size, the use of RE-MD is limited to the study of oligomerization of small peptide fragments ( Nishino et al, 2005 ; Liang et al, 2007 , 2008 ; Wei et al, 2007 ; De Simone and Derreumaux, 2010 ; Nishikawa et al, 2019 ). In the case of β2m, MD simulations have been used to study the dynamics of the native monomer ( Ma and Nussinov, 2003 ; Deng et al, 2006 ; Fogolari et al, 2011 ; Chandrasekaran and Rajasekaran, 2016 ), the oligomerization process of selected amyloidogenic β2m peptide sequences ( Liang et al, 2007 ; Zheng et al, 2008 ; Fang et al, 2009a ), and provide complementary information to that obtained through in vitro experiments ( Gumral et al, 2013 ; Chong et al, 2015 ; Torbeev et al, 2015 ; Camilloni et al, 2016 ; Hall et al, 2016 ; Brancolini et al, 2018 ). Another enhanced sampling scheme is the so-called metadynamics ( Laio and Parrinello, 2002 ).…”

“…In recent years, the Asp76Asn mutant became a valuable model system to study β2m aggregation ( Valleix et al, 2012 ; Chong et al, 2015 ; de Rosa et al, 2015 ; Chandrasekaran and Rajasekaran, 2016 ; Leri et al, 2016 ; Loureiro et al, 2017 ; Le Marchand et al, 2018 ). The reason is twofold.…”

“…Secondly, since this mutant is the causative agent of a fatal hereditary systemic amyloidosis, it has a clear biological and biomedical relevance. The Asp76Asn mutant has, therefore, been the subject of several experimental and computational studies aimed at explaining its increased aggregation propensity and aggregation mechanism ( Chong et al, 2015 ; de Rosa et al, 2015 ; Chandrasekaran and Rajasekaran, 2016 ; Leri et al, 2016 ; Loureiro et al, 2017 ; Le Marchand et al, 2018 ).…”

Analysis of molecular dynamics simulations of 10-residue peptide, chignolin, using statistical mechanics: Relaxation mode analysis and three-dimensional reference interaction site model theory

“…The Ham group applied the AD method to their studies about the amyloid-beta protein: hydrohobicity [149], dimerization [150], aggregation [151][152][153], and self-assembly [154]. They also studied about the amyloidogenic potential of β-2-Microglobulin mutant [155], and protein-ligand binding thermodynamics [156].…”

Assessing the effect of D59P mutation in the DE loop region in amyloid aggregation propensity of β2‐microglobulin: A molecular dynamics simulation study

“…The strand D has been reported to play a key role in the edgeedge strand association and fibril assembly. 18 Chong et al 19 hydrophobic core residues to solvent in the folded I T -state was reported. 12 The above-mentioned studies emphasized the importance of I T -state for wt β2m and D59P.…”