Structural Analysis of a Trimer of β2-Microgloblin Fragment by Molecular Dynamics Simulations

Abstract

A peptide b 2 -m 21À31 , which is a fragment from residue 21 to residue 31 of b 2 -microgloblin, is experimentally known to self-assemble and form amyloid fibrils. In order to understand the mechanism of amyloid fibril formations, we applied the replica-exchange molecular dynamics method to the system consisting of three fragments of b 2 -m 21À31 . From the analyses on the temperature dependence, we found that there is a clear phase transition temperature in which the peptides aggregate with each other. Moreover, we found by the free energy analyses that there are two major stable states: One of them is like amyloid fibrils and the other is amorphous aggregates.

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

“…A popular workaround to overcome the limitations of classical MD is the replica exchange (RE) method ( Nishino et al, 2005 ; Liang et al, 2007 , 2008 ; Wei et al, 2008 ; De Simone and Derreumaux, 2010 ; Nishikawa et al, 2019 ), in which several MD trajectories (the so called replicas) run in parallel at different temperatures, and moves between adjacent replicas are attempted based on a Monte Carlo Metropolis rule ( Nishino et al, 2005 ; Liang et al, 2007 , 2008 ; Wei et al, 2008 ; De Simone and Derreumaux, 2010 ; Nishikawa et al, 2019 ). By limiting trapping in local energy minima, RE allows equilibrium sampling of the conformational landscape.…”

“…However, since the constant temperature trajectories are discontinuous, the RE sampling method loses kinetic information. 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 ).…”

Interdiction in the Early Folding of the p53 DNA-Binding Domain Leads to Its Amyloid-Like Misfolding

“…Finally, the relatively simple algorithm presented here has sufficed to successfully predict primary contacts within the SCM so far. However, specific issues critical for drug design, such as identifying the optimal interdiction molecules and fully characterizing their interactions, will probably require a more sophisticated approach, including state-of-the-art molecular dynamics [ 80 ].…”