Solvent sensitivity of protein aggregation in Cu, Zn superoxide dismutase: a molecular dynamics simulation study

Abstract

Misfolding and aggregation of Cu, Zn Superoxide Dismutase (SOD1) is often found in amyotrophic lateral sclerosis (ALS) patients. The central apo SOD1 barrel was involved in protein maturation and pathological aggregation in ALS. In this work, we employed atomistic molecular dynamics (MD) simulations to study the conformational dynamics of SOD1 monomer in different concentrations of trifluoroethanol (TFE). We find concentration dependence unusual structural and dynamical features, characterized by the local unfolding of SOD1. This partially unfolded structure is characterized by the exposure of hydrophobic core, is highly dynamic in nature, and is the precursor of aggregation seen in SOD1. Our computational studies supports the hypothesis of the formation of aggregation 'building blocks' by means of local unfolding of apo monomer as the mechanism of SOD1 fibrillar aggregation. The non-monotonic TFE concentration dependence of protein conformational changes was explored through simulation studies. Our results suggest that altered protein conformation and dynamics within its structure may underlie the aggregation of SOD1 in ALS.

Computational Insights of Unfolding of N-Terminal Domain of TDP-43 Reveal the Conformational Heterogeneity in the Unfolding Pathway

“…However, a slight decrease in Nc of NTD was observed during the simulation. Thus, to accelerate the unfolding process of NTD, the all-atom MD simulations in the presence of 8 M DMSO for 500 ns were carried out with higher temperatures, very similar to our previous studies (Prakash et al, 2018a , b ).…”

Unfolding Transitions of Peripheral Subunit Binding Domains Show Cooperative Behavior

“…This 37-residue construct is similar to Munoz construct with broad unfolding temperatures ranging from 295 to 335 K . Recently, similar unfolding experiments were carried out to study the effect of temperature and denaturants such as trifluoroethanol (TFE) on the unfolding and conformational stability, flexibility, and dynamics of N-terminal domain of TAR DNA-binding protein-43 (TDP-43), Cu/Zn superoxide dismutase (SOD1), − and RNA recognition motifs (RRMs) of TDP-43 . These studies revealed the conformational heterogeneity within the structures related to the distinct structural stabilities and unfolding dynamics of these proteins and shed light on the misfolding and aggregation of these proteins.…”

Insights into the Conserved Regulatory Mechanisms of Human and Yeast Aging

“…In humans, the coexistence of several pathologies is driven by the multipolar effects of unhealthy or premature aging [12,13]. Neurodegenerative diseases like Alzheimer's, frontotemporal dementia, and Parkinson's are prevalent and occur among the age group of 45-64 [14][15][16] establishing that the continuum of broad neurodegenerative diseases is clinically, pathologically, and mechanistically associated with age with a spectrum of overlapping clinical symptoms [17][18][19][20].…”