Comparative structural and conformational studies on H43R and W32F mutants of copper–zinc superoxide dismutase by molecular dynamics simulation

Muneeswaran, Gurusamy; Kartheeswaran, Subramanian; Muthukumar, Kaliappan; Dharmaraj, Christopher D.; Karunakaran, C.

doi:10.1016/j.bpc.2013.11.010

Cited by 18 publications

(8 citation statements)

References 41 publications

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“…The allosteric pathway thus identified is comprised mainly of backbone-mediated interactions, which explains its lack of susceptibility to ALS-causing mutations, as previously discussed . The exception is the H43 residue, which participates in the interactions with its side chain and is the target of at least one known ALS-causing mutation …”

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confidence: 89%

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An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation

Souza

Thallmair

Marrink

et al. 2019

J. Phys. Chem. Lett.

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Several different mutations of the protein copper, zinc superoxide dismutase (SOD1) produce the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The molecular mechanism by which the diverse mutations converge to a similar pathology is currently unknown. The electrostatic loop (EL) of SOD1 is known to be affected in all of the studied ALS-linked mutations of SOD1. In this work, we employ a multiscale simulation approach to show that this perturbation corresponds to an increased probability of the EL detaching from its native position, exposing the metal site of the protein to water. From extensive atomistic and coarse-grained molecular dynamics (MD) simulations, we identify an allosteric pathway that explains the action of the distant G93A mutation on the EL. Finally, we employ quantum mechanics/molecular mechanics MD simulations to show that the opening of the EL decreases the Zn(II) affinity of the protein. As the loss of Zn(II) is at the center of several proposed pathogenic mechanisms in SOD1-linked ALS, the structural effect identified here not only is in agreement with the experimental data but also places the opening of the electrostatic loop as the possible main pathogenic effect for a significant number of ALS-linked SOD1 mutations.

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confidence: 89%

“…22 The exception is the H43 residue, which participates in the interactions with its side chain and is the target of at least one known ALS-causing mutation. 35…”

mentioning

confidence: 99%

An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation

Souza

Thallmair

Marrink

et al. 2019

J. Phys. Chem. Lett.

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“…We used steady state tryptophan fluorescence, far UV CD and FTIR spectroscopy to characterize these different proteins. SOD1 is a single tryptophan protein (Trp32), in which the tryptophan residue has been shown to be partially buried 23 . The role of Trp32 within the sequence segment 30 KVWGSIKGL 38 of high aggregation propensity has been investigated before 24 .…”

Section: Cu Deficient H121f Behaves Like Wt Sod1 Whereas Zn Deficient H72f Behaves Like Apomentioning

confidence: 99%

The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model

Sannigrahi

Chowdhury

Das

et al. 2021

eLife

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Aggregation of Cu-Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, ALS. Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a 'co-factor derived membrane association model' wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association mediated toxic aggregation and survival time scale after ALS diagnosis.

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“…Accumulation of misfolded proteins plays an important role in the process of the ALS. Mounting experimental studies have focused on elucidating the mechanism for how mutations promote SOD1 misfolding and aggregation. − On the computational side, a growing number of molecular dynamics (MD) studies have been carried out to investigate the local unfolding and structural properties of full-length SOD1 protein and its various mutants. − These experimental and computational studies have greatly enhanced our understanding of the role of different mutations on the aggregations and structural stability of SOD1 protein, while the aggregation property at the atomic level is not well understood.…”

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confidence: 99%

Critical Nucleus Structure and Aggregation Mechanism of the C-terminal Fragment of Copper–Zinc Superoxide Dismutase Protein

Zou

Sun

Zhu

et al. 2016

ACS Chem. Neurosci.

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The aggregation of the copper-zinc superoxide dismutase (SOD1) protein is linked to familial amyotrophic lateral sclerosis, a progressive neurodegenerative disease. A recent experimental study has shown that the (147)GVIGIAQ(153) SOD1 C-terminal segment not only forms amyloid fibrils in isolation but also accelerates the aggregation of full-length SOD1, while substitution of isoleucine at site 149 by proline blocks its fibril formation. Amyloid formation is a nucleation-polymerization process. In this study, we investigated the oligomerization and the nucleus structure of this heptapeptide. By performing extensive replica-exchange molecular dynamics (REMD) simulations and conventional MD simulations, we found that the GVIGIAQ hexamers can adopt highly ordered bilayer β-sheets and β-barrels. In contrast, substitution of I149 by proline significantly reduces the β-sheet probability and results in the disappearance of bilayer β-sheet structures and the increase of disordered hexamers. We identified mixed parallel-antiparallel bilayer β-sheets in both REMD and conventional MD simulations and provided the conformational transition from the experimentally observed parallel bilayer sheets to the mixed parallel-antiparallel bilayer β-sheets. Our simulations suggest that the critical nucleus consists of six peptide chains and two additional peptide chains strongly stabilize this critical nucleus. The stabilized octamer is able to recruit additional random peptides into the β-sheet. Therefore, our simulations provide insights into the critical nucleus formation and the smallest stable nucleus of the (147)GVIGIAQ(153) peptide.

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Comparative structural and conformational studies on H43R and W32F mutants of copper–zinc superoxide dismutase by molecular dynamics simulation

Cited by 18 publications

References 41 publications

An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation

An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation

The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model

Critical Nucleus Structure and Aggregation Mechanism of the C-terminal Fragment of Copper–Zinc Superoxide Dismutase Protein

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